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  • 2000-2004  (35)
  • 1985-1989  (599)
  • 1920-1924
  • pharmacokinetics  (634)
  • 101
    Electronic Resource
    Electronic Resource
    Effect of urapidil on steady-state serum digoxin concentration in healthy subjects (1989)
    Springer
    European journal of clinical pharmacology 37 (1989), S. 193-194 
    Details
    ISSN: 1432-1041
    Keywords: urapidil ; digoxin ; blood drug level ; pharmacokinetics ; drug absorption/-interaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In an open, randomized, two-period change-over study the effect of urapidil, an antihypertensive agent, on steady-state serum digoxin levels was investgated in 12 healthy male volunteers. The subjects were given digoxin 0.25 mg once daily for 4 days to produce a steady-state digoxin level in serum. At the end of that time the subjects received either digoxin monotherapy or digoxin and concomitant treatment with urapidil 60 mg b.d. for a further 4 days. Subsequently the treatments were changed over. The absorption characteristics Cmax and tmax of digoxin were not altered by concomitant urapidil treatment. The geometric mean and nonparametric 95% confidence limits of digoxin relative bioavailability were 97% (93%–103%). Therefore, concomitant administration of urapidil with digoxin treatments did not appear to alter the rate and extent of absorption of the glycoside.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00558231
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  • 102
    Electronic Resource
    Electronic Resource
    Total and free steady-state plasma levels and pharmacokinetics of nifedipine in patients with terminal renal failure (1989)
    Springer
    European journal of clinical pharmacology 37 (1989), S. 185-189 
    Details
    ISSN: 1432-1041
    Keywords: nifedipine ; renal failure ; pharmacokinetics ; protein binding ; blood pressure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The total and free steady-state plasma levels of nifedipine in patients with renal failure have been compared with those in subjects with normal renal function. Studies were done after administration of nifedipine 10 mg t.d.s. p.o. for 5 days, after i.v. infusion of 4·4 mg, and after a single 10 mg oral dose. The systemic clearance of nifedipine after a single i.v.-dose was higher in subjects with renal insufficiency (854 ml/min) than in those with normal renal function (468 ml/min). After the single oral dose the AUC (6100 ng·min·ml−1) and maximum plasma concentration (75.0 ng·ml−1) were lower than in subjects with normal renal function (19300 ng·ml−1; 122 ng·ml−1). The plasma protein binding of nifedipine averaged 95.5% in normal subjects and 94.8% in patients with renal failure. Although free and total steady-state plasma levels of nifedipine tended to be somewhat lower than normal in renal failure, the changes in pharmacokinetics and decreased protein binding of nifedipine did not result in a significantly different steady-state plasma level of the drug. The blood pressure response to a given plasma nifedipine level appeared to be enhanced in renal failure.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00558229
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  • 103
    Electronic Resource
    Electronic Resource
    The disposition and kinetics of intravenous N-acetylcysteine in patients with paracetamol overdosage (1989)
    Springer
    European journal of clinical pharmacology 37 (1989), S. 501-506 
    Details
    ISSN: 1432-1041
    Keywords: N-acetylcysteine ; paracetamol ; acetaminophen overdose ; pharmacokinetics ; liver damage ; adverse reactions ; dose modifications
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Seventeen patients received standard treatment with intravenous N-acetylcysteine for 18 episodes of severe poisoning with paracetamol (acetaminophen). The dose of N-acetylcysteine was 150 mg/kg given in 15 min followed by 50 mg/kg in 4 h and 100 mg/kg over the next 16 h. Liver damage was absent or mild on 13 occasions (ALT〈500 µ/l) and severe on 5 (ALT〉1000 µ/l). Total plasma N-acetylcysteine was estimated by HPLC. The mean maximum plasma concentration after the initial loading dose was 554 mg/l. Concentrations then fell rapidly and after 12 h a mean steady-state level of about 35 mg/l was maintained. When the infusion was discontinued N-acetylcysteine disappeared with a half-life of 5.7 h. The mean steady-state volume of distribution, AUC, mean residence time and total clearance were 536 ml/kg, 1748 mg·h·l−1, 2.91 h and 3.18 ml·min−1·kg−1. These values are generally consistent with those previously reported with much smaller doses and the disposition of N-acetylcysteine does not appear to be dose-dependent. The elimination of N-acetylcysteine was not impaired in the patients with severe liver damage, and the pharmacokinetic variables and plasma concentrations were similar in patients with and without hepatotoxicity. The dosage schedule for intravenous N-acetylcysteine should probably be modified since adverse reactions invariably occur early when plasma concentrations are at their highest, and liver damage was prevented just as effectively at the lowest as at the highest Cmax. High initial concentrations of N-acetylcysteine can be avoided with simple alternative regimens based on the kinetic data of this study.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00558131
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  • 104
    Electronic Resource
    Electronic Resource
    Application of a radioreceptor assay in a pharmacokinetic study of oxitropium bromide in healthy volunteers after single i.v., oral and inhalation doses (1989)
    Springer
    European journal of clinical pharmacology 37 (1989), S. 507-512 
    Details
    ISSN: 1432-1041
    Keywords: oxitropium bromide ; pharmacokinetics ; radioreceptor assay ; side-effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Oxitropium bromide (OXBR) is a new anticholinergic drug, which is expected to be useful in the treatment of nocturnal asthma. The only pharmacokinetic data were obtained with the14C-labelled compound. A sensitive radioreceptor assay for the determination of unlabelled OXBR in plasma was developed, based on competition between OXBR and3H-N-methylscopolamine for binding to muscarinic receptors. OXBR was isolated from plasma by ion-pair extraction and re-extraction. Active metabolites present in significant amounts might interfere in the assay, but this was not the case for OXBR metabolites. Detection limits were 300 pg·ml−1 and 3 ng·ml−1 for plasma and urine, respectively. For the latter no extraction step was required. The single dose pharmacokinetics of OXBR was studied following inhalation (3 mg), oral (2 mg) and i.v. (1 mg) administration to 12 men, following an open, cross-over design. After i.v. administration the kinetic parameters were: Vc 38.4 l; t1/2α 5.3 min; t1/2β 142 min; AUC 8.9 h·ng·ml−1; renal excretion 50.2%, k10 3.5 l·h−1 and total clearance 1874 ml/min. The apparent bioavailabilities were 0.48% and 12.4% by the oral and inhalation routes, respectively, based on the cumulative renal excretion. There were moderate adverse reactions due to the anticholinergic properties of the drug.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00558132
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  • 105
    Electronic Resource
    Electronic Resource
    Absorption and elimination of bismuth from oral doses of tripotassium dicitrato bismuthate (1989)
    Springer
    European journal of clinical pharmacology 37 (1989), S. 533-536 
    Details
    ISSN: 1432-1041
    Keywords: bismuth ; absorption ; elimination ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of bismuth subcitrate were studied in plasma and urine under conditions of single and multiple dosing (28–56 days) using atomic absorption technique. Single dose plasma pharmacokinetics showed peak concentrations of 5.5–57.5 µg·l−1 (mean=24.7 µg·l−1), reached between 30 and 60 min post dosing with an apparent biphasic elimination pattern. Multiple dose studies showed a continuing rise in plasma concentration and urine excretion rate reaching apparent steady-state levels over 7–29 days (mean=18 days). Washout studies in 6 individuals reciprocated accumulation. Maximum equilibrated plasma levels of 7.6–58.3 µg·l−1 (mean=38.3 µg·l−1) were well below those associated with encephalopathy. The half-life of bismuth elimination was 20.7 days. Present patterns of intermittent dosing with bismuth are unlikely to be associated with bismuth accumulation despite slow accumulation and elimination.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00558139
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  • 106
    Electronic Resource
    Electronic Resource
    Single dose and steady-state pharmacokinetics of 4 mg and 8 mg oral salbutamol controlled-release in patients with bronchial asthma (1989)
    Springer
    European journal of clinical pharmacology 37 (1989), S. 49-52 
    Details
    ISSN: 1432-1041
    Keywords: salbutamol ; asthma ; controlled-release formulation ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Fifteen patients with asthma were given salbutamol controlled-release (SCR) 4 mg or 8 mg twice daily for seven days, in a randomised double-blind cross-over design. Plasma salbutamol levels were measured after the first and fifteenth doses for a 12 h period following drug ingestion. At steady-state the geometric mean values for Cmax were 8.2 ng/ml for 4 mg, and 16.1 ng/ml for 8 mg. Median tmax values were 300 and 240 min respectively. The geometric mean AUC (0–12) were 4507 ng·min·ml−1 and 8980 ng·min/ml. Peak to trough fluctuation ratios were 0.577 and 0.572. There were no significant differences between 4 mg or 8 mg formulations, for any of the parameters measured, after appropriate corrections for dose. The concentration-time profiles at steady-state showed little fluctuation in plasma salbutamol levels over the twelve hour dosing interval. These results show that 4 mg and 8 mg formulations of SCR provide smooth plasma profiles at steady-state with a twice daily dosing regime.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00609424
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  • 107
    Electronic Resource
    Electronic Resource
    First dose and steady-state pharmacokinetics of oxcarbazepine and its 10-hydroxy metabolite (1989)
    Springer
    European journal of clinical pharmacology 37 (1989), S. 69-74 
    Details
    ISSN: 1432-1041
    Keywords: oxcarbazepine ; pharmacokinetics ; drug metabolism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of oxcarbazepine (a new anticonvulsant which is a congener of carbamazepine) and of its 10-hydroxy metabolite were studied at the outset of therapy in 8 adult epileptics comedicated with other anticonvulsants. The pharmacokinetic study was repeated under steady-state conditions after 3 months of drug intake in 6 of these subjects. The plasma elimination half-life of oxcarbazepine appeared to lie in the range 1.0–2.5 h, and that of its 10-hydroxy metabolite averaged 8.4 h. The apparent oral clearance of the parent drug (averaging 2.51·kg−1·h−1) was high enough to suggest substantial presystemic elimination. The oral clearance fell after 3 months of drug intake, but the half-lives of the drug and metabolite showed no statistically significant change over this time. Steady-state plasma levels of both drug and metabolite were linearly related to drug dose, metabolite levels averaging 9 times those of the parent substance.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00609428
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  • 108
    Electronic Resource
    Electronic Resource
    Haemodynamic and pharmacokinetic evaluation of alfuzosin in man. A dose ranging study and comparison with prazosin (1989)
    Springer
    European journal of clinical pharmacology 37 (1989), S. 53-58 
    Details
    ISSN: 1432-1041
    Keywords: alfuzosin ; prazosin ; alpha1-adrenoceptor antagonist ; noradrenaline ; pharmacokinetics ; pharmacodynamics ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In an open dose ranging study with random inclusion of placebo, alfuzosin (α1-adrenoceptor antagonist) 1, 2.5 and 5 mg was administered to 6 healthy volunteers, 3 of the volunteers received 10 mg alfuzosin. Supine systolic blood (SBP) pressure was not reduced by alfuzosin although significant increases occurred in supine heart rate (HR) after 2.5 and 5 mg. In the standing position, SBP was reduced at 2 and 4 h with 5 mg alfuzosin; significant increases in HR occurred following 1, 2.5 and 5 mg at 2, 4, 6 and 8 h after administration. Exercise SBP was not reduced; diastolic blood pressure was significantly reduced at 4 and 6 h with 5 mg alfuzosin. More marked effects were seen in the 3 subjects who received 10 mg alfuzosin. After 1 and 5 mg, tmax ranged from 1–2 h; Cmax (4.1 to 20.8 ng · ml−1; AUC (0–24) 20 to 132 ng · ml−1 · h (1 and 5 mg respectively) increased progressively with dose indicating dose dependent kinetics; no significant changes occurred in the visual analogue scale for sedation. A comparison of alfuzosin 5 mg, prazosin 1 mg and placebo each administered for 4 days, indicated that alfuzosin did not significantly reduce standing SBP on either Day 1 or Day 4; prazosin reduced SBP at 2 and 4 h on Day 1 and 6 h on Day 4 compared to placebo. Standing HR was increased by alfuzosin at 2 h on Day 1 and Day 4; increases occurred with prazosin at 2, 4, 6 and 8 h on Day 1 and 6 h on Day 4. Supine plasma noradrenaline increased with alfuzosin and prazosin at 2 and 4 h on Days 1 and 4; the increases were not significantly different. The plasma elimination half-life (t1/2) for alfuzosin was 3.4 h and 3.1 h after acute and chronic administration; (t1/2) for prazosin was 2.6 and 2.9 h. In conclusion alfuzosin causes small reductions in systolic blood pressure, accompanied by a dose dependent increase in heart rate in the supine and standing position and following exercise.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00609425
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  • 109
    Electronic Resource
    Electronic Resource
    Metabolism and disposition of intravenously administered acetyl-L-carnitine in healthy volunteers (1989)
    Springer
    European journal of clinical pharmacology 37 (1989), S. 59-63 
    Details
    ISSN: 1432-1041
    Keywords: acetyl-L-carnitine ; renal clearance ; pharmacokinetics ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of acetyl-L-carnitine hydrochloride were investigated in 6 healthy volunteers of both sexes after i.v. injection of 500 mg of the drug, expressed as inner salt. Plasma concentrations and urinary excretion of acetyl-L-carnitine (A), L-carnitine (B) and total acid soluble L-carnitine fraction were evaluated over a period lasting from 24 h before to 48 h after the administration. Plasma concentrations of A increased quickly after administration and then declined reaching base values within 12 h. Conversely, plasma concentrations of B rose more slowly, reaching a peak in 30–60 min, and then declined to base values within 24 h. Most of the injected dose of acetyl-L-carnitine was recovered in the urine during the first 24 h after administration as B and A. Mean renal clearance of both A and B during the first 12 h after injection was higher than the base values, suggesting the presence of a saturable tubular reabsorption process which may counterbalance major changes occurring in plasma concentrations of L-carnitine pattern.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00609426
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  • 110
    Electronic Resource
    Electronic Resource
    The pharmacokinetics of low-dose dexamethasone in congenital adrenal hyperplasia (1989)
    Springer
    European journal of clinical pharmacology 37 (1989), S. 75-77 
    Details
    ISSN: 1432-1041
    Keywords: dexamethasone ; congenital adrenal hyperplasia ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of dexamethasone, given at low dose, were studied in 13 patients with congenital adrenal hyperplasia (CAH) to ascertain whether kinetics differed in this inherited disorder of cortisol metabolism from those seen in healthy individuals. Changes in plasma dexamethasone concentration after intravenous bolus, measured using a simple novel radioimmunoassay, were well described by a two-compartment open model with first-order kinetics. Values for λ2: 0.206 h−1, t1/2: 3.53 h, Vc: 24.41 and f: 0.64 were similar to those previously reported for normal subjects. There were considerable interindividual differences in parameter values and Cmaxp.o. (range 22–67 nmol/l). As suppression of the hypothalamo-pituitary-adrenal axis correlates with plasma dexamethasone levels, this variability may partly explain the differing dose and dose schedule requirements necessary to achieve adequate therapeutic control in the clinical management of CAH.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00609429
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  • 111
    Electronic Resource
    Electronic Resource
    Zero-order absorption and linear disposition of oral colchicine in healthy volunteers (1989)
    Springer
    European journal of clinical pharmacology 37 (1989), S. 79-84 
    Details
    ISSN: 1432-1041
    Keywords: colchicine ; pharmacokinetics ; oral administration ; zero-order absorption ; systemic availability ; dose dependency ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of colchicine has been studied in nine healthy male volunteers after oral doses of 0.5, 1, and 1.5 mg as tablets. Plasma and urine samples were collected over 48 h and analysed for colchicine by radioimmunoassay. Individual colchicine concentration profiles in plasma and urine were well described by a two-compartment open model with zero-order input. Considering the absorption variables as specific to each experiment, the lag time (0–0.35 h) and duration (0.39–2.38 h) of absorption were found to be independent of dose, while the zero-order rate constant of absorption (k0) increased linearly with dose. Disposition variables were taken as common to the three experiments, except in six subjects in whom renal excretion varied significantly across experiments in a dose-independent manner. For seven subjects the terminal half-life was 19.4 h, the oral apparent volume of distribution at steady-state (Vss/f) was 691 l, and the oral systemic clearance (CL/f) was 33.1 l·h−1. In the two other subjects, the values were unreliable, but the estimated terminal half-life was greater than 48 h, Vss/f ranged from 1690 to 3480 l, and CL/f was in the range of the other subjects in 1 subject, and it was about 15l·h−1 in the other. In the latter subject, these estimates, together with the observation that plasma concentration reached a plateau at 2 to 5 h after ingestion, suggest enterohepatic cycling of colchicine. Overall, the disposition of colchicine was linear in the dose range 0.5–1.5 mg, with a long terminal half-life, and absorption obeyed zero-order kinetics, with k0 proportional to dose.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00609430
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  • 112
    Electronic Resource
    Electronic Resource
    Influence of hyperlipidic food on the kinetics of slow-release formulations of theophylline (1989)
    Springer
    European journal of clinical pharmacology 37 (1989), S. 85-90 
    Details
    ISSN: 1432-1041
    Keywords: theophylline ; sustained-release formulation ; bioavailability ; fatty food ; dumping effect ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A cross-over study of kinetics has been undertaken in 12 healthy adults volunteers using two sustained-release theophylline products that allow once a day dosing (Theo-Dur tablets and Dilatrane A.P. bead filled capsules) to compare the i.v. pharmacokinetic profiles when taken with an hyperlipidic meal and a balanced standard meal. Each subject took part in four phases in randomised order, corresponding to all possible combinations of the products and the types of meal. Each phase involved a single dose of 9 to 11 mg·kg−1 theophylline administered at 20.00 h, at the beginning of the meal, with 100 ml water. The two formulations were found to be bioequivalent with both types of meal. Taken with a balanced meal, the mean parameters were similar; for Theo-Dur and Dilatrane A.P. they were respectively: Cmax: 11.32 mg·l−1 which plateaued from 8 to 10 h after dosing and 10.9 mg·l−1, which plateaued after 6 to 10 h; AUC 230 mg·h·l−1 and 220 mg·h·l−1; and MRT 18.2 h and 17.7 h. After the hyperlipidic meal the values for Theo-Dur and Dilatrane A.P. respectively, were: Cmax 10.9 mg·l−1 at 12 h and 11.3 mg·l−1 at 10 h; AUC 237 mg·h·l−1 and 227 mg·h·l−1; and MRT 19.2 h and 18.9 h. In spite of a decrease in the absorption rate, which led to a shift to the right of about 2 h of the plasma concentration-time curve, the bioavailability of both formulations were not significantly modified by a hyperlipidic meal as compared to a balanced meal. The shift of the curve with fatty food was not clinically important, as there was no dumping effect. The main difference between the two formulations was seen during the absorption phase, which was linear and less variable with Dilatrane A.P. and sigmoidal with Theo-Dur. This was observed with both types of meal.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00609431
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  • 113
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of midazolam in patients recovering from cardiac surgery (1989)
    Springer
    European journal of clinical pharmacology 37 (1989), S. 161-166 
    Details
    ISSN: 1432-1041
    Keywords: midazolam ; benzodiazepine ; pharmacokinetics ; biotransformation ; surgery ; prolonged recovery
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of midazolam has been studied in patients recovering from cardiac surgery, who required sedation for postoperative mechanical ventilation. Twelve males (mean age 64.5 years) with severe heart disease received an infusion of midazolam 15 mg·h−1 for 4 h, starting 1 to 3 h post surgery. Multiple blood samples were collected from each patient during the infusion and up to 48–93 h after it. The pharmacokinetic parameters of midazolam were determined using both moment analysis and the program NONMEM. The average terminal half-life was 10.6 h. The prolonged elimination was mainly due to a decrease in its metabolic clearance (0.25 l·min−1). The maintenance infusion dose of midazolam in such patients should be reduced. The time to recovery after stopping an infusion depends upon the amount of drug in the body at that time and a simulation of the plasma concentrations after various infusion regimens suggests that recovery will be delayed after prolonged (〉48 h) administration of midazolam to these patients. However, after shorter infusions (〈12 h), redistribution of the drug away from the site of action was still occurring and recovery would be expected to be relatively rapid.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00558225
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  • 114
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of ketoprofen enantiomers in cholecystectomy patients: influence of probenecid (1989)
    Springer
    European journal of clinical pharmacology 37 (1989), S. 589-594 
    Details
    ISSN: 1432-1041
    Keywords: ketoprofen ; probenecid ; cholecystectomy ; enantiomers ; glucuroconjugates ; stereoselectivity ; T-tube patients ; biliary excretion ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Ketoprofen (KT), a 2-arylpropionic acid nonsteroidal antiinflammatory drug, is administered as a racemate. Previous reports suggest stereoselective biliary excretion of KT enantiomers. This hypothesis was tested by administering 50 mg racemic KT to five patients who required bile drainage following cholecystectomy surgery. Subsequently, to study the influence of probenecid (PB), an inhibitor of KT renal elimination, on the biliary excretion, 1000 mg PB was administered 1.5 h before KT to the same patients. The unchanged and conjugated (as glucuronides) KT enantiomers were measured in plasma, urine and bile. In general, KT enantiomers had different plasma concentration-time curves. As compared to normal subjects, these patients had comparable AUCs and shorter t1/2s. Biliary concentrations of conjugated S-KT were greater than R-KT. Nevertheless, the total cumulative biliary excretion of conjugated KT did not exceed 2% of the dose ruling out this pathway as a significant route of KT elimination. There was a positive and significant correlation between the cumulative urinary excretion of conjugated KT enantiomers and creatinine clearance. Although PB did not influence the pattern of stereoselectivity of KT, it increased AUC and prolonged t1/2 of the enantiomers. While reducing cumulative urinary excretion, PB increased total biliary elimination of conjugated KT enantiomers. This, however, did not totally compensate for the reduced urinary excretion. It is suggested that the impaired conjugation of KT caused by PB administration may result in the augmentation of other, otherwise minor, metabolic pathways.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00562550
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  • 115
    Electronic Resource
    Electronic Resource
    Circadian variation in the pharmacokinetics of verapamil (1989)
    Springer
    European journal of clinical pharmacology 37 (1989), S. 613-615 
    Details
    ISSN: 1432-1041
    Keywords: verapamil ; pharmacokinetics ; circadian rhythm
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Circadian variation in the metabolism of verapamil was investigated in 10 patients with stable angina pectoris during treatment with sustained-release verapamil 360 mg at 08.00 h or 22.0 h. No major difference in exercise parameters was found. During the evening dosage schedule a significantly greater bioavailability (AUC) and a prolonged time to peak concentration was found. During the night (24.00 h–06.00 h) the half-life of verapamil was significantly longer than during the day (16.00 h–22.00 h). These differences in pharmacokinetics may be due to reduced hepatic blood flow at night or to circadian variation in hepatic microsomal metabolism.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00562555
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  • 116
    Electronic Resource
    Electronic Resource
    Mean residence time for drugs subject to enterohepatic cycling (1989)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 17 (1989), S. 327-345 
    Details
    ISSN: 1573-8744
    Keywords: enterohepatic recirculation ; pharmacokinetics ; hepatic extraction ; area under the first moment curve ; model ; bile ; mean residence time ; mean absorption time ; formulations
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract A physiologically realistic model of enterohepatic cycling (EHC) which includes separate liver and gallbladder compartments, discontinuous gallbladder emptying and first-order absorption from both an oral formulation and secreted bile (ka po and ka b, respectively) has been developed. The effect of EHC on area under the first-moment curve (AUMC) of drug concentration in plasma and on parameters derived from the AUMC was investigated. Unlike AUC, AUMC is dependent on the time and time-course of gallbladder emptying, increasing as the interval between gallbladder emptying increases. Consequently, mean residence time (MRT) is also a time-dependent parameter. Analytical solutions for MRTiv and MRTpo were derived. Mean absorption time (MAT = MRTpo — MRTivj is also time-dependent, contrary to findings previously published for a model of EHC with a continuous time lag. MAT is also dependent on k a po , k a b and the hepatic extraction ratio. The difference between MRT po s two formulations with unequal k a po values may deviate from the difference in the inverse of their absorption rate constants. Implications for design and interpretation of pharmacokinetic studies include (i) MAT values may be dominated by the time-course of recycling rather than the time-course of the initial absorption, depending on the extent of EHC and (ii) the unpredictable nature of the time of gallbladder emptying will contribute to intrasubject variability in derived parameters during crossover studies. Knowledge of the extent of EHC is invaluable in deciding whether modification of the in vitro release characteristics of an oral formulation will have any effect on the overall time-course of absorption in vivo. Techniques to monitor or control gallbladder emptying may be helpful for reducing variability in pharmaco-kinetic studies for compounds which are extensively cycled in bile.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01061900
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  • 117
    Electronic Resource
    Electronic Resource
    The kinetic disposition and dosage regimen for carbenicillin in buffalo calves (1989)
    Springer
    Veterinary research communications 13 (1989), S. 389-394 
    Details
    ISSN: 1573-7446
    Keywords: buffalo ; carbenicillin ; pharmacokinetics ; therapeutics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The distribution half-life, elimination half-life, apparent volume of distribution and total body clearance of carbenicillin in healthy buffalo calves following a single intravenous administration (50 mg/kg) were 0.057±0.005 h, 1.688±0.11 h, 0.185±0.021 L kg-1 and 75.97±6.519 ml kg-1 h-1 respectively. A satisfactory dosage regimen for carbenicillin in buffalo calves was calculated to be 56 mg/kg followed by 52 mg/kg body weight repeated at 6 h intervals.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00346071
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    The pharmacokinetics of volatile anesthetic agent elimination: A theoretical study (1989)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 17 (1989), S. 109-123 
    Details
    ISSN: 1573-8744
    Keywords: anesthetics, gases ; pharmacokinetics ; volatile anesthetics ; inhalation agents
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The theoretical groundwork for a rate constant formulation of inhaled anesthetic elimination kinetics is discussed. In an effort to simulate recent experimental results a linear flow-limited five-compartment model was used comprising lung, vessel-rich tissue, muscle, nonvisceral fat, and an additional compartment, marrow-visceral fat whose functional existence recently has been experimentally demonstrated. Hypothetical but plausible parameters for the marrow-visceral fat compartment were used. The theoretically predicted values were in good agreement with experimental results suggesting that this model is appropriate for the elimination kinetics of agents that are not metabolized to any significant degree. Simple approximate expressions for the rate constants were also derived and were in reasonable agreement with experimental results. The model was also employed to clarify the effect of anesthetic duration on subsequent elimination kinetics.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01059090
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  • 119
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    Drug- or hormone-induced adaptation: Model of adrenergic hypersensitivity (1989)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 17 (1989), S. 347-364 
    Details
    ISSN: 1573-8744
    Keywords: hypersensitivity ; propranolol ; pharmacokinetics ; pharmacodynamics ; modeling ; β receptor ; adrenergic stimulation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract A pharmacokinetic/pharmacodynamic model of hypersensitivity to adrenergic stimulation following abrupt withdrawal of chronic β blockade was developed. The model employs the Hill equation, a term which describes the competition between isoproterenol and l- propranolol for β receptors, and a kinetic term which characterizes the appearance and disappearance rates of up-regulated β receptors. The model predicted peak chronotropic hyperresponsiveness to isoproterenol 48 hr following abrupt withdrawal of chronic treatment with daily propranolol doses of 160 mg, and a drug half-life of 3.5 hr. The model also predicted that increasing the dose rate and prolonging the half-life of propranolol delayed and decreased the extent of adrenergic hypersensitivity. The time-course of adrenergic hypersensitivity simulated by our model was in excellent agreement with that observed in studies which were published earlier by our laboratory. The model underestimated the extent of adrenergic hypersensitivity. The results of our simulation are consistent with a β agonist-receptor-effector system, which involves spare receptors, amplification of response by second and third messengers, and β agonist-antagonist-induced receptor regulation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01061901
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  • 120
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    Effect of propranolol on the myocardial contractility of normotensive and spontaneously hypertensive rabbits: Relationship of pharmacokinetics and pharmacodynamics (1989)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 17 (1989), S. 551-570 
    Details
    ISSN: 1573-8744
    Keywords: propranolol ; pharmacokinetics ; pharmacodynamics ; myocardial contractility ; hypertensive ; rabbit
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Myocardial contractility of normotensive and spontaneously hypertensive rabbits was determined following an iv bolus injection of propranolol HCl. Left ventricular pressure and dimension were used to calculate the contractility parameters of (dP/dt) max ,maximum fiber shortening velocity V cf , and the slope of the end systolic pressure-end systolic volume line (ESP-ESV line). Hypertension was induced by a methoxamine HCl iv infusion which mimicked the cardiac effects seen in essential hypertension. Propanolol caused a significant decrease in all contractility parameters (p〈0.05)within 15min after administration, with a peak effect occurring after 30–35 mins. The pharmacokinetics and pharmacodynamics of propranolol were fit using Hill's equation in conjunction with the concentration of drug in the theoretical effect compartment. The normotensive group of rabbits had a calculated EC (50) of 12.7 ng/ml, while the hypertensive group had an EC 50 of 6.9 ng/ml,indicating that the hypertensive rabbits were much more sensitive to the propranolol than the normotensive group. In addition, the normotensive group of rabbits demonstrated a much different pharmacokinetic-pharmacodynamic relationship than that of the hypertensive group, indicating that the hypertensive state of the animal has a significant effect upon the concentration-effect relationship.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01071349
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  • 121
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    The influence of assay variability on pharmacokinetic parameter estimation (1989)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 17 (1989), S. 571-592 
    Details
    ISSN: 1573-8744
    Keywords: pharmacokinetics ; variability ; parameter estimation ; modeling ; nonlinear regression ; Wagner-Nelson method ; mixed effects models
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The impact of assay variability on pharmacokinetic modeling was investigated. Simulated replications (150) of three “individuals” resulted in 450 data sets. A one-compartment model with first-order absorption was simulated. Random assay errors of 10, 20, or 30% were introduced and the ratio of absorption rate (K a )to elimination rate (K e )constants was 2, 10, or 20. The analyst was blinded as to the rate constants chosen for the simulations. Parameter estimates from the sequential method (K e )estimated with log-linear regression followed by estimation of K a and nonlinear regression with various weighting schemes were compared. NONMEM was run on the 9 data sets as well. Assay error caused a sizable number of curves to have apparent multicompartmental distribution or complex absorption kinetic characteristics. Routinely tabulated parameters (maximum concentration, area under the curve, and, to a lesser extent, mean residence time) were consistently overestimated as assay error increased. When K a /K e =2,all methods except NONMEM underestimated K e ,overestimated K a ,and overestimated apparent volume of distribution. These significant biases increased with the magnitude of assay error. With improper weighting, nonlinear regression significantly overestimated K e when K a /K e ,=20. In general, however, the sequential approach was most biased and least precise. Although no interindividual variability was included in the simulations, estimation error caused large standard deviations to be associated with derived parameters, which would be interpreted as interindividual error in a nonsimulation environment. NONMEM, however, acceptably estimated all parameters and variabilities. Routinely applied pharmacokinetic estimation methods do not consistently provide unbiased answers. In the specific case of extended-release drug formulations, there is clearly a possibility that certain estimation methods yield K a and relative bioavailability estimates that would be imprecise and biased.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01071350
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  • 122
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    Effects of two isomeric 1-aminoadamantanes on the membrane anisotropy and on alpha- and gamma-motoneurones excitability (1989)
    Springer
    Journal of neural transmission 1 (1989), S. 153-164 
    Details
    ISSN: 1435-1463
    Keywords: Aminoadamantanes ; pharmacokinetics ; CNS ; membrane anisotropy ; excitability ; spinal alpha- and gamma-motoneurons
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The structure-activity relationship of two isomeric 1-aminoadamantanes, 1-C-ethylaminoadamantane (D 174) and 1-amino-3-ethyladamantane (D 175), on membrane anisotropy and the excitability of neurons was studied in the CNS of the rat and in the decerebrated cat. Mass spectrometric analysis showed that after a single, 40 mg/kg dose, D 174 and D 175 were unevenly distributed within the CNS of the rat, moreover the distribution pattern of the two substances was different. As measured by fluorescence depolarization in controls the membrane anisotropy was found to be higher in the older parts as compared with the younger parts of the CNS. After i.p. application of 40 mg/kg the membrane anisotropy was reduced in the cortex by D 174, whereas D 174 and D 175 increased the rigidity in striatal membranes. If cortical membranes were incubated with the substances, the fluidizing effect of D 174 was more prominent than that of D 175. In the decerebrated cat only D 174 in a dose of 5 mg/kg i.p. raised the discharge of spinal alpha-motoneurones significantly. The results suggest that the membrane architecture is more affected by D 174 as compared with D 175 which is reflected by a greater effect on membrane anisotropy as well as on the activity of spinal alpha-motoneurones.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02248665
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  • 123
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    Verapamil disposition and cardiovascular effects in elderly patients after single intravenous and oral doses (1989)
    Springer
    Cardiovascular drugs and therapy 3 (1989), S. 417-425 
    Details
    ISSN: 1573-7241
    Keywords: verapamil ; elderly ; pharmacokinetics ; cardiovascular effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Pharmacokinetics and pharmacodynamics of verapamil were studied in 11 elderly subjects (age=79.67±4.74 years) and in 11 middle-aged subjects (age=45±11.37 years) following intravenous (IV), single oral, and long-term oral administration. Plasma verapamil concentrations were determined using high-pressure liquid chromatography (HPLC). Twenty-four hour dynamic Holter electrocardiographic (ECG) recordings were employed to study heart rate (HR) and P-R interval. No difference in plasma half-life, distribution volume, body clearance, and area under the curve (AUC) was observed between the two groups after IV and oral verapamil administration. Blood pressure (BP) and HR were significantly reduced after verapamil IV administration in the elderly group only (p〈0.05, p〈0.01, respectively). After single and long-term oral administration, variable HR and BP responses were observed in both groups. The P-R prolongation following both IV and single oral doses exhibited a delay with respect to the peak plasma concentration, inducing a definite hysteresis loop. The slope of P-R variations (using a linear pharmacodynamic model) was greater in the elderly both after IV and single oral verapamil administration, but statistical significance was obtained only after the single oral dose (p〈0.05). In the elderly group, after long-term oral administration, there was a significant prolongation of the P-R interval (p〈0.0001) with respect to the corresponding time point of the 24-hour predrug period. Such variations in pharmacodynamic parameters in the elderly did not, however, cause any clinical problem. In conclusion, verapamil seems to be well tolerated in the elderly as well as in younger patients at similar dosages. However, its use in the elderly requires careful clinical evaluation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01858113
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    Calcium channel antagonists: part VI: Clinical pharmacokinetics of first and second-generation agents (1989)
    Springer
    Cardiovascular drugs and therapy 3 (1989), S. 482-497 
    Details
    ISSN: 1573-7241
    Keywords: pharmacokinetics ; calcium antagonists ; liver disease ; renal disease ; hepatic enzymes ; metabolites
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A survey of the pharmacokinetic properties of the three prototypical calcium antagonist agents shows that they have in common a very high rate of hepatic first-pass metabolism with, in the case of verapamil and diltiazem, the formation of an active metabolite that affects the dose during chronic therapy. Therefore, the major factor altering the pharmacokinetic properties and the dose of the drug required is the capacity of the liver to metabolize the drug, which in turn depends on the hepatic blood flow and the activity of the hepatic metabolizing systems. Hence liver disease, a low cardiac output, and coadministration of certain drugs inducing or inhibiting the hepatic enzymes, all indirectly affect the pharmacokinetic properties of the calcium antagonists. There are also other potential drug interactions of a kinetic or dynamic nature that may arise. In general, renal disease has little effect on the pharmacokinetics of calcium antagonists.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01865507
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    Effects of cardiovascular disease on pharmacokinetics (1989)
    Springer
    Cardiovascular drugs and therapy 3 (1989), S. 711-730 
    Details
    ISSN: 1573-7241
    Keywords: cardiovascular disease ; pharmacokinetics ; antiarrhythmics ; inotropics ; betablockers ; diuretics ; antihypertensives
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The pathophysiologic changes occurring in cardiovascular disease can affect the kinetics of drugs in several different ways. The present review examines these modifications and the underlying mechanisms. The kinetics of specific agents, such as antiarrhythmic, antihypertensive, cardiotonic, and other drugs are considered, and the clinical implications are outlined. The clinician should be aware of these modifications, because they require an adjustment of the dosage regimen. A rational basis for a correct therapeutic choice can be provided by adequate knowledge of these modifications.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01857622
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  • 126
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    A phase I trial of recombinant human interferon-γ in patients with Kaposi's sarcoma and the acquired immunodeficiency syndrome (AIDS) (1989)
    Springer
    Journal of clinical immunology 9 (1989), S. 351-361 
    Details
    ISSN: 1573-2592
    Keywords: Interferon-γ ; Kaposi's sarcoma ; human immunodeficiency virus (HIV) ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract A Phase I study of recombinant interferon-gamma (rIFN-γ) was conducted to determine the toxicity and pharmacokinetics of this lymphokine in acquired immunodeficiency syndrome (AIDS) patients with Kaposi's sarcoma (KS). Sixteen patients with AIDS/KS were entered into a fixed-dose trial at either 0.001, 0.01, 0.1, or 1.0 mg/m2 of rIFN-γ. rIFN-γ was initially administered either as a single 24-hr continuous iv infusion or as a single im injection, followed 4 days later by a 10-day course of daily therapy by the same route. Following a 1-week washout period, this sequence of administration was then repeated, with the drug given by the alternate route. Pharmacokinetic analysis of the 1.0-mg/m2 group revealed that peak serum levels of up to 153 U/ml occurred 2–4 hr after im injection and that steady-state levels of up to 40 U/ml were reached approximately 7–12 hr after beginning iv infusion. Dose-related toxicities in this trial included fever, headache, fatigue, nausea, and hepatitis, all of which were most severe at the two highest doses. Dose-dependent depression of the total white blood-cell (WBC) count, affecting both granulocytes and lymphocytes, was the most common laboratory abnormality. Natural killer (NK)-cell activity was slightly enhanced at a dose of 0.1 mg/m2 but suppressed at 1.0 mg/m2 of drug; monocyte-mediated cytotoxicity, in contrast, was significantly increased only at the highest dose. No dose-related changes were noted in KS lesions, HLA-DR expression by peripheral blood mononuclear cells, lymphocyte blastogenesis, or the ability to culture cytomegalovirus (CMV) from body fluids. We conclude that a maximally tolerated dose (MTD) for this drug is in the range of 0.1–1.0 mg/m2 and that at least modest evidence of systemic immunomodulation may be seen when rIFN-γ is given at doses at or near this MTD.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00918667
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    Polyvinyl Alcohol–Methyl Acrylate Copolymers as a Sustained-Release Oral Delivery System (1989)
    Springer
    Pharmaceutical research 6 (1989), S. 844-847 
    Details
    ISSN: 1573-904X
    Keywords: polyvinyl alcohol–methyl acrylate copolymers ; crystalline ; low crystalline ; phenylpropanolamine ; sustained release ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Low crystalline and crystalline polyvinyl alcohol–methyl acrylate (PVA-MA) copolymers were examined, because of their excellent flow and compressibility properties, as matrices for sustained-release tablets using phenylpropanolamine hydrochloride (PPA.HC1) as a model drug. Crystallinity of the copolymer affected the release characteristics from the tablet. Tablets made with low-crystalline PVA-MA provided sustained release of PPA, both in vitro and in vivo in dogs. PPA absorption from the low-crystalline PVA-MA tablet formulation was biphasic. An initial rapid phase was followed by a second, slower absorption phase which continued over 16 hr. Plasma PPA concentrations then declined with a half-life roughly parallel to the oral immediate-release half-lives. Oral bioavailability from the low-crystalline PVA-MA tablet formulation was 78.8 ± 3.9%.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015900303534
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    High-Performance Liquid Chromatographic Determination and Pharmacokinetics of Methyl N-[5[[4-(2-Pyridinyl)-l-piperazinyl]carbonyl]-1H-benzimidazol-2-yl] Carbamate (CDRI Compound 81-470), a New Anthelmintic Agent in Rats (1989)
    Springer
    Pharmaceutical research 6 (1989), S. 991-993 
    Details
    ISSN: 1573-904X
    Keywords: CDRI compound 81-470 ; anthelmintic ; high-performance liquid chromatography (HPLC) ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015910000325
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    Effect of the Immunomodulator Tilorone on the in Vivo Acetylation of Procainamide in the Rat (1989)
    Springer
    Pharmaceutical research 6 (1989), S. 477-480 
    Details
    ISSN: 1573-904X
    Keywords: acetylation ; immunomodulators ; interferon inducers ; pharmacokinetics ; procainamide ; tilorone
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Interferon and interferon inducers have been found to inhibit cytochrome P-450-dependent metabolism in animals and man. The effect of these agents on the acetylation of drugs has not been previously reported. Since these agents stimulate the reticuloendothelial system, together with the abundance of N-acetyltransferase in the reticuloendothelial system, it was hypothesized that these immunomodulators may affect drug acetylation. To test this hypothesis, the effect of tilorone (a synthetic interferon inducer) on the in vivo acetylation of procainamide was examined in the rat. Pretreatment with tilorone hydrochloride (50 mg/kg) 48 hr prior to the administration of procainamide hydrochloride (50 mg/kg) resulted in a 32% increase in the urinary recovery of N-acetylprocainamide and a 35% increase in the metabolic clearance of procainamide to N-acetylprocainamide. These data indicate that interferon inducers increase the N-acetylation of drugs in vivo.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015964306318
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    Liposomal Formulation Eliminates Acute Toxicity and Pump Incompatibility of Parenteral Cyclosporine (1989)
    Springer
    Pharmaceutical research 6 (1989), S. 601-607 
    Details
    ISSN: 1573-904X
    Keywords: liposome ; cyclosporine ; acute toxicity ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The currently available intravenous dosage form of cyclosporine (CSA), Sandimmune I.V., contains the vehicle, Cremophor EL, which has been implicated in producing anaphylactic reactions in man and animals. This formulation also leaches through silicone tubing, an important component of some automatic drug delivery devices, causing pump dysfunction. In an attempt to develop a less toxic and pump-compatible formulation of CSA, suitable for intrarenal infusion in a canine transplant model, we compared the acute toxicity, pharmacokinetics, and pump compatibility of emulsified (CSA/emulsion) and liposomal (CSA/liposomes) CSA preparations with those of Sandimmune I.V. and CSA dissolved in ethanol vehicle (CSA/alcohol) in healthy, unoperated dogs. Animals receiving Sandimmune I.V. demonstrated marked acute toxicity despite progressive 10-fold dose reduction and 〉50-fold prolongation of infusion duration. One of two animals receiving CSA/emulsion and both dogs receiving emulsion vehicle alone exhibited a moderately severe reaction, while five of seven dogs receiving CSA/alcohol demonstrated immediate, mild reactions. No discernible adverse reactions occurred in any animal receiving CSA/liposomes. Systemic disposition of CSA/alcohol and CSA/liposomes was similar. In contrast to the liposomal vehicle, the emulsion vehicle produced a marked, early weight gain and substantial decrease in tensile strength of the pump tubing, both of which would adversely affect pump function. These results provide the first description of liposomal CSA toxicology and pharmacokinetics in a large animal model and may lead to the successful development of a less toxic parenteral CSA formulation for systemic and local pump-based administration.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015905615404
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    Route of Administration and Sex Differences in the Pharmacokinetics of Aspirin, Administered as Its Lysine Salt (1989)
    Springer
    Pharmaceutical research 6 (1989), S. 660-666 
    Details
    ISSN: 1573-904X
    Keywords: aspirin ; pharmacokinetics ; intramuscular ; sex differences ; rate of absorption
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract One thousand milligrams of aspirin, as its lysine salt, was administered intravenously, orally, and intramuscularly to nine male and nine female young healthy adult volunteers. After intravenous injection mean (±SD) values of clearance, steady-state volume of distribution, and terminal half-life were 12.2 ± 2.2 ml/min/kg, 0.219 ± 0.042 liter/kg, and 15.4 ± 2.5 min, respectively, with no differences between males and females. Following oral administration aspirin was absorbed more quickly in females than in males (mean absorption times of 16.4 and 21.3 min, respectively) although the bioavailability, 54%, was the same in both groups. In contrast, following intramuscular administration, aspirin was absorbed more slowly in females than males (mean absorption times of 97 and 53 min, respectively) but again the bioavailability, 89%, was the same in both groups. The data suggest that in the female the intramuscular injection is going into fat. Salicylic acid concentration–time profiles showed a less pronounced sex difference and were comparable among the three routes of administration.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015978104017
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    Pharmacokinetics of Ketorolac and p-Hydroxyketorolac Following Oral and Intramuscular Administration of Ketorolac Tromethamine (1989)
    Springer
    Pharmaceutical research 6 (1989), S. 62-65 
    Details
    ISSN: 1573-904X
    Keywords: ketorolac ; p-hydroxyketorolac ; oral ; intramuscular ; pharmacokinetics ; dose proportionality
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Ketorolac tromethamine (KT), a potent analgesic with cyclooxygenase inhibitory activity, was administered in an open, randomized, single-dose study of Latin-square design to 12 healthy male volunteers. Doses of 30 mg oral (po) and 30, 60, and 90 mg intramuscular (im) KT were administered in solution. Plasma samples were analyzed for ketorolac (K) and its inactive metabolite, p-hydroxyketorolac (PHK), by reversed-phase high-performance liquid chromatography (HPLC). The 30-mg im dose was found to be similar to the 30-mg po dose with respect to total AUC values for both K and PHK. The amount of PHK circulating in plasma was very low as judged by AUC ratios (PHK/K × 100) of 1.9 and 1.5% for the 30-mg po and im doses, respectively. The rate of absorption of K and formation of PHK, as determined by C max and T max values, was significantly slower following the im doses. Total AUC and C max for K and PHK increased linearly with dose after im administration of 30, 60, and 90 mg of KT. The mean plasma half-life of K was remarkably consistent between po and im administration and was independent of dose, ranging from 5.21 to 5.56 hr. The plasma metabolic profile was similar following both routes of administration and graded im doses.
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    URL: http://dx.doi.org/10.1023/A:1015803803650
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    Binding of Sulfonamides to Carbonic Anhydrase: Influence on Distribution Within Blood and on Pharmacokinetics (1989)
    Springer
    Pharmaceutical research 6 (1989), S. 203-209 
    Details
    ISSN: 1573-904X
    Keywords: pharmacokinetics ; carbonic anhydrase ; sulfonamides ; binding ; erythrocytes
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Four new aromatic sulfonamides were synthesized and purified by standard techniques. Two were unsubstituted, primary sulfonamides and two possessed substituents on the sulfonamide nitrogen. The affinity of the inhibitors for the enzyme carbonic anhydrase was determined in terms of the inhibitory potency, which was found to be dependent on the presence of an unsubstituted sulfonamide group. Binding studies were performed in erythrocyte suspensions using a range of concentrations and the unbound, extracellular concentrations were determined by high-performance liquid chromatographic (HPLC) assay. The dissociation constant of binding and the total binding capacity of the erythrocytes were estimated by nonlinear regression using a two-site binding model. The affinity of the compounds for erythrocytes reflected their inhibitory potency against the enzyme. Binding to plasma proteins was more dependent on lipophilicity and pK a and was stronger for the substituted sulfonamides. Pharmacokinetic studies in rats showed that the unsubstituted sulfonamides with a high affinity for carbonic anhydrase in erythrocytes have longer half-lives and lower clearance values than the substituted sulfonamides which were more strongly bound to plasma proteins. However, comparison of unbound clearance values showed that the variations in molecular structure, which produced differences in carbonic anhydrase binding and in distribution, also produced variations in susceptibility to elimination processes.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015957315462
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  • 134
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    Experimental Animal Models for Studying Antimicrobial Pharmacokinetics in Otitis Media (1989)
    Springer
    Pharmaceutical research 6 (1989), S. 279-285 
    Details
    ISSN: 1573-904X
    Keywords: otitis media ; pharmacokinetics ; amoxicillin ; trimethoprim ; sulfamethoxazole
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Antimicrobial treatment of otitis media, especially drug dosing considerations, is largely empiric, with few reported pharmacologic studies of drug distribution into the middle ear. A chinchilla animal model of serous and purulent otitis media has been used for some time to investigate mechanisms of disease pathogenesis. This model was adapted to investigate the penetration of amoxicillin, trimethoprim, and sulfamethoxazole into middle ear effusion. Purulent otitis media was produced by direct middle ear inoculation with type 7F Streptococcus pneumoniae. Serous otitis media was produced by eustachian tube obstruction using silastic sponge or Coeflex cement, but the Coeflex caused an undesirable local inflammatory response. The three antibiotics were administered to chinchillas with serous and purulent middle ear effusion. Plasma and ear fluid drug concentrations were measured by liquid chromatography and demonstrated the value of this model in assessing antibiotic penetration.
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    URL: http://dx.doi.org/10.1023/A:1015938205892
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    Structure–Pharmacokinetic Relationships in a Series of Valpromide Derivatives with Antiepileptic Activity (1989)
    Springer
    Pharmaceutical research 6 (1989), S. 683-689 
    Details
    ISSN: 1573-904X
    Keywords: valpromide ; valproic acid ; antiepileptic activity ; SAR ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The following valpromide (VPD) derivatives were synthesized and their structure–pharmacokinetic relationships explored: ethylbutylacetamide (EBD), methylpentylacetamide (MPD), propylisopropylacetamide (PID), and propylallylacetamide (PAD). In addition, the anticonvulsant activity of these compounds was evaluated and compared to that of VPD, valnoctamide (VCD), and valproic acid (VPA). MPD, the least-branched compound had the largest clearance and shortest half-life of all the amides investigated and was the least active. All other amides had similar pharmacokinetic parameters. Unlike the other amides, PID and VCD did not metabolize to their respective homologous acids and were the most active compounds. Our study showed that these amides need an unsubstituted β position in their aliphatic side chain in order to biotransform to their homologous acids. An amide which is not metabolized is more potent as an anticonvulsant than its biotransformed isomer. All amides were more active than their respective homologous acids. In this particular series of aliphatic amides, which were derived from short-branched fatty acids, the anticonvulsant activity was affected by the pharmacokinetics in general and by the biotransformation of the amide to its homologous acid in particular. This amide–acid biotransformation appeared to be dependent upon the chemical structure, especially upon the substitution at position β of the molecule.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015934321764
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  • 136
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    Dose-Ranging Pharmacokinetics of Zidovudine (Azidothymidine) in the Rat (1989)
    Springer
    Pharmaceutical research 6 (1989), S. 734-736 
    Details
    ISSN: 1573-904X
    Keywords: dose ranging ; pharmacokinetics ; zidovudine ; azidothymidine ; rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015954926307
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  • 137
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    Electronic Resource
    Pharmacokinetics of Sulfasalazine Metabolites in Rats Following Concomitant Oral Administration of Riboflavin (1989)
    Springer
    Pharmaceutical research 6 (1989), S. 1067-1072 
    Details
    ISSN: 1573-904X
    Keywords: sulfasalazine ; metabolites ; riboflavin ; azo-reduction ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Sulfasalazine, 60 mg/kg, was administered orally to groups of rats (n = 4) along with 1, 5, or 10 mg/kg of riboflavin. Plasma and urine were assayed for 5-aminosalicylic acid, acetyl-5-aminosalicylic acid, sulfapyridine, and acetyl-sulfapyridine using an HPLC method. The mean percent of dose recovered as total metabolites in urine was significantly greater (α = 0.01) for the group receiving 10 mg/kg riboflavin compared to the controls or the group receiving 1 mg/kg riboflavin. Plasma AUC and C max values were also significantly greater (α = 0.05) for the 10 mg/kg riboflavin group. These results suggest that at higher doses, a significant fraction of riboflavin reaches the colon intact and stimulates more efficient reduction of the azo bond in sulfasalazine. Since the concentrations of 5-ASA achieved in the colon may be directly related to the efficacy of sulfasalazine in treating inflammatory bowel disease, concomitant administration of riboflavin may enhance sulfasalazine's efficacy in humans.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015938706685
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  • 138
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    Electronic Resource
    Prediction of the Distribution Volumes of Cefazolin and Tobramycin in Obese Children Based on Physiological Pharmacokinetic Concepts (1989)
    Springer
    Pharmaceutical research 6 (1989), S. 486-491 
    Details
    ISSN: 1573-904X
    Keywords: cefazolin ; tobramycin ; volume of distribution ; pharmacokinetics ; intravenous administration ; obese children
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract So as to estimate the appropriate dose of antibacterial drugs in obese children, prediction of the volume of distribution in these children was attempted based on physiological pharmacokinetic concepts which had been constructed from results in normal-weight children. Serum concentration–time data after intravenous drip infusions of tobramycin and cefazolin were analyzed using noncompartmental analysis of obese children in whom the degree of obesity ranged from 30 to 80%. Volume of distribution at steady state (V ss) per total body weight of tobramycin was significantly less than that for normal-weight children (P 〈 0.05), whereas the value of cefazolin was almost equal to that for normal-weight children. The equation to express the difference of Vss between cefazolin and tobramycin obtained in normal-weight children failed in obese children, suggesting that there is a large decrease in the extracellular space in obese children exceeding the interindividual variations in normal-weight children. The V ss value (liter) for tobramycin was predicted by using the equation 0.261 · {ideal body weight (kg) + 0.4 · [total body weight (kg) – ideal body weight (kg)]}. The V ss value of cefazolin was predicted to be 0.3 · (predicted V ss of tobramycin) + 0.052 · total body weight (kg). A good correlation between the predicted and the observed V ss values was obtained.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015968407226
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  • 139
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    Electronic Resource
    Efficiency of Drug Targeting: Steady-State Considerations Using a Three-Compartment Model (1989)
    Springer
    Pharmaceutical research 6 (1989), S. 367-372 
    Details
    ISSN: 1573-904X
    Keywords: drug targeting ; site-specific delivery ; steady state ; pharmacokinetics ; pharmacodynamic model
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Physiological models have often been used to investigate the processes involved in drug targeting. Such a model is used to investigate some aspects of drug targeting, including the pharmacodynamics of therapeutic and toxic effects. A simple pharmacodynamic model is incorporated in a three-compartment pharmacokinetic model. Conventional administration and drug targeting are compared at steady state for the same degree of therapeutic effect. The efficiency of drug targeting is quantified as the ratio (TA) of the rates of administration of free drug or of a drug–carrier complex required to achieve this effect. Also, the ratios of drug concentrations in the toxicity compartment (DTI) or of the consequent degree of toxic effects (TI) are used to compare conventional administration with drug targeting. The kinetic characteristics of the drug–carrier complex, rate of elimination, and rate of free drug release, influence TA but not DTI or TI. The importance of these characteristics depends on the cost and toxicity of the drug–carrier complex or of the carrier alone. The pharmacodynamics of the free drug in both the target and the toxicity compartments have an important influence on TI but not on TA or DTI. As the pharmacological selectivity of the drug increases, so does TI. However, a drug with good pharmacological selectivity may not be suitable for drug targeting. TI is also very dependent on the shape of the effect–concentration curves, particularly that for toxicity. While TA increases as the rate of elimination of free drug from either central or target compartments increases, TI may actually be reduced if release of free drug is not confined to the target compartment.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015971113161
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  • 140
    Electronic Resource
    Electronic Resource
    Pharmacokinetics and Oral Bioavailability of Scopolamine in Normal Subjects (1989)
    Springer
    Pharmaceutical research 6 (1989), S. 481-485 
    Details
    ISSN: 1573-904X
    Keywords: pharmacokinetics ; scopolamine ; drug disposition ; motion sickness drug
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The pharmacokinetics and bioavailability of scopolamine were evaluated in six healthy male subjects receiving 0.4 mg of the drug by either oral or intravenous administration. Plasma and urine samples were analyzed using a radioreceptor binding assay. After iv administration, scopolamine concentrations in the plasma declined in a biexponential fashion, with a rapid distribution phase and a comparatively slow elimination phase. Mean and SE values for volume of distribution, systemic clearance, and renal clearance were 1.4 ± 0.3 liters/kg, 65.3 ± 5.2 liters/hr, and 4.2 ± 1.4 liters/hr, respectively. Mean peak plasma concentrations were 2909.8 ± 240.9 pg/ml following iv administration and 528.6 ± 109.4 pg/ml following oral administration. Elimination half-life of the drug was 4.5 ± 1.7 hr. Bioavailability of the oral dose was variable among subjects, ranging between 10.7 and 48.2%. The variability in absorption and poor bioavailability of oral scopolamine indicate that this route of administration may not be reliable and effective.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015916423156
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  • 141
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    Electronic Resource
    Pharmacokinetics of Platinum in Cancer Patients Treated with Carboplatin in Combination with High-Dose Methotrexate (1989)
    Springer
    Pharmaceutical research 6 (1989), S. 492-496 
    Details
    ISSN: 1573-904X
    Keywords: carboplatin ; pharmacokinetics ; platinum, total, ultrafilterable ; urinary excretion ; cancer patients ; chemotherapy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The pharmacokinetics of platinum was investigated in 10 cancer patients treated with a 1-hr infusion of 300 mg/m2 of carboplatin which was given 2–4 days after the administration of 100 mg/kg (20-mg/kg bolus and 80-mg/kg intravenous infusion) of methotrexate. Platinum was analyzed in the samples by flameless atomic absorption spectrophotometry. The concentration vs time data for total platinum in plasma followed a two-compartment model and the mean (and SE) values for β, TBC, V c, and RC were 0.0827 (0.22) hr−1, 2.355 (0.252) liters/hr · m2, 10.74 (0.62) liters/m2, and 2.405 (0.228) liters/hr · m2, respectively. There was no significant change in the creatinine clearance or TBC with repeated treatment. The ultrafilterable platinum which was measured in the plasma of two patients constituted 82 and 11.3% of the total platinum at 1 and 24 hr, respectively, and the data conformed to the one-compartment model. The mean (SE) values for t β, TBC, and V d for free platinum were 1.844 (0.208) hr, 4.583 (1.059) liters/hr · m2, and 11.88 (1.45) liters/m2, respectively. The above data are in good agreement with those reported earlier for platinum following the administration of carboplatin as a single agent. These results suggest that high-dose methotrexate therapy, when administered 2–4 days before carboplatin, does not affect the pharmacokinetics of platinum in the plasma.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015920524065
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  • 142
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    Electronic Resource
    The Effect of End-to-Side Portacaval Shunt on Cyclosporine Pharmacokinetics in Rats (1989)
    Springer
    Pharmaceutical research 6 (1989), S. 255-257 
    Details
    ISSN: 1573-904X
    Keywords: cyclosporine ; pharmacokinetics ; rats ; portacaval shunt
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015977820005
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  • 143
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    A Retrospective Analysis of Fenoldopam Renal Excretion in 65 Subjects: Evidence for Possible Intrarenal Formation of Fenoldopam from Its Metabolites (1989)
    Springer
    Pharmaceutical research 6 (1989), S. 702-705 
    Details
    ISSN: 1573-904X
    Keywords: fenoldopam ; renal excretion ; reversible metabolism ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Clinical studies have suggested that the dopamine DA1 agonist, fenoldopam, may exhibit nonlinear renal excretion in humans. A retrospective population pharmacokinetic analysis of the renal excretion of fenoldopam and one of its major metabolites, fenoldopam-8-sulfate, was conducted in 65 healthy volunteers to examine this phenomenon. Fenoldopam-8-sulfate exhibited a mean (±SE) renal plasma clearance of 129 ± 4 ml/min, which was independent of its AUC. In contrast, fenoldopam renal plasma clearance ranged from 2220 to 150 ml/min and decreased nonlinearily with increasing fenoldopam AUC. Fenoldopam renal clearance was characterized as a function of fenoldopam AUC using a nonlinear saturation model. The analysis predicted an initial maximal renal clearance of 2852 ml/min, which decreased to 78 ml/min at maximal inhibition. The fenoldopam AUC required to half-saturate fenoldopam renal clearance was 5.2 ng × hr/ml. The elevated clearance values for fenoldopam, beyond normal physiologic limits for renal blood flow in man, suggest that intrarenal formation of fenoldopam from one or more of its circulating metabolites may be contributing to the observed nonlinear decreases in fenoldopam renal excretion. Preliminary data from our laboratory suggest that in vivo desulfation of fenoldopam-8-sulfate to fenoldopam does occur in the dog.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015990506743
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  • 144
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    Electronic Resource
    Current models in pharmacokinetics: Applications in veterinary pharmacology (1989)
    Springer
    Veterinary research communications 13 (1989), S. 141-157 
    Details
    ISSN: 1573-7446
    Keywords: models ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Major advances in developing models for pharmacokinetic studies have been made in recent years, and different approaches can now be employed. These include the use of (1) compartmental models, (2) non-compartmental models, (3) physiological models, (4) population pharmacokinetic models, and (5) pharmacokinetic-pharmacodynamic models. Each of these approaches has both advantages and disadvantages. The important question of which of these is ‘ideal’ in veterinary pharmacokinetics has no simple answer. The selection and application of any one approach would depend on a number of factors, such as (1) the purpose of the study, (2) physicochemical properties and actions of drug, (3) specificity and sensitivity of the analytical methodology, (4) species of the animal, and (5) availability of funds. This paper reviews the models available for pharmacokinetic studies and indicates their possible application in veterinary pharmacology.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00346724
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  • 145
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    Electronic Resource
    Disposition and dosage regimen of cephaloridine in calves (1989)
    Springer
    Veterinary research communications 13 (1989), S. 325-329 
    Details
    ISSN: 1573-7446
    Keywords: blood ; cattle ; cephaloridine ; chemotherapy ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The disposition and dosage regimen of cephaloridine were investigated in healthy calves following a single intramuscular administration of 10 mg/kg. The absorption halflife, climination halflife, apparent volume of distribution and total body clearance were 0.107±0.025 h, 2.08±0.14 h, 0.70±0.07L kg-1 and 235.8±21.9 ml kg-1 h-1, respectively. Therapeutic plasma levels (≥1 μg/ml) were maintained for up to 7 h. A satisfactory intramuscular dosage regimen for cephaloridine in calves would be 10 mg/kg repeated at 8 h intervals.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00420839
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  • 146
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    Electronic Resource
    Disposition kinetics and urinary excretion of gentamicin in buffalo bulls (Bubalus bubalis) (1989)
    Springer
    Veterinary research communications 13 (1989), S. 331-337 
    Details
    ISSN: 1573-7446
    Keywords: blood ; buffalo ; chemotherapy ; gentamicin ; pharmacokinetics ; urine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The disposition kinetics and urinary excretion of gentamicin sulphate were studied in young buffalo bulls following a single intramuscular administration of the drug at 5 mg kg-1 body weight. The time course of the serum gentamicin concentration was adequately described by the one-compartment open model. The values of the absorption and elimination halflives were 12.2±2.2 and 167.0±29.7 min respectively. The apparent volume of distribution was 0.29±0.01 L kg-1. During the first 12 h, 63% of the total administered dose was excreted in urine. On the basis of the kinetic data, a satisfactory intramuscular dosage regimen for gentamicin sulphate would be at least 6 mg kg-1 body weight repeated at 8 h intervals.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00420840
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  • 147
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    Electronic Resource
    Disposition of125I-labeled recombinant human tumor necrosis factor in the tumor-bearing mouse (1989)
    Springer
    Biotherapy 1 (1989), S. 7-18 
    Details
    ISSN: 1573-8280
    Keywords: disposition ; distribution ; excretion ; Meth A sarcoma ; pharmacokinetics ; tumornecrosis factor
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Disposition of [125I]rHu-TNF was elucidated in BALB/c mice bearing Meth A fibrosarcoma 7 days after transplantation. Afteri.v. administration, [125I]rHu-TNF measured by radioactivity and immunoreactivity biphasically decreased in plasma. Tumor level of [125I]rHu-TNF was the maximum at 1 h, then decreased and finally remained essentially constant. After i.t. administration, plasma level reached the maximum at 1 h. Tumor level decreased quickly and then became essentially constant. [125I]rHu-TNF was suggested to be degraded to small fragments in the tumor. Significant distribution of [125I]rHu-TNF was found in the kidney, lung, liver and tumor. Most tissue levels decreased with time in parallel with plasma levels. [125I]rHu-TNF radioactivity was found in proximal convoluted tubules of kidney and in those areas of tumor consisting of degenerating cells with pyknotic nuclei. Urine contained most of administered radioactivity, which being neither immunoreactive nor protein-bound.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02170131
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  • 148
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    Pharmacokinetics of the enantiomers of terbutaline after repeated oral dosing with racemic terbutaline (1989)
    New York, NY [u.a.] : Wiley-Blackwell
    Chirality 1 (1989), S. 174-177 
    Details
    ISSN: 0899-0042
    Keywords: pharmacokinetics ; terbutaline ; enantiomers ; human ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Terbutaline is a β2-agonist and administered as the racemic mixture. The pharmacokinetics of the separate enantiomers differ with respect to degree of absorption and clearance. In the present study, repeated doses of racemic terbutaline were given to six healthy volunteers. Plasma was analyzed for the concentrations of the two enantiomers. The observed plasma concentrations at steady state differed from those predicted from the values observed after single dose administration of the separate enantiomers. The difference between the observed and predicted values can be tentatively explained by a combined influence of (-)-terbutaline on the absorption of (+)-terbutaline and the influence of (+)-terbutaline on the elimination of (-)-terbutaline. The results have implications for the interpretation of effect/concentration studies with terbutaline, but do not affect the doses used in clinical practice.
    Additional Material: 2 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/chir.530010213
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  • 149
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    Electronic Resource
    Preliminary evaluation of potential anti-epileptic drugs by single dose electrophysiological and pharmacological studies in patients (1988)
    Springer
    Journal of neural transmission 72 (1988), S. 259-266 
    Details
    ISSN: 1435-1463
    Keywords: Anti-epileptic drugs ; pharmacokinetics ; EEG ; photosensitivity ; drug interactions
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary In phase 1 evaluation of potential anti-epileptic drugs (AEDs), insufficient attention has perhaps been directed to the transition from single, and multi-dose studies in normal volunteers to clinical trials of some weeks duration in patients. Acute single dose studies in epileptic patients already receiving AEDs may reduce avoidable errors in early controlled trials. Acute single dose studies provide the opportunity of obtaining some preliminary evidence of efficacy by observing the effects of the drug on quantified epileptiform EEG discharges, both those occurring spontaneously in long term telemetric recordings and those elicited by standardised photic stimulation in susceptible subjects. The pharmacokinetics of the new drug may be profoundly influenced by the comedication (as illustrated by lamotrigine, the half life of which varies by a factor of 10 depending on comedication). Conversely, the new drug may so influence metabolism of the comedication that the results of add-on trials may be virtually uninterpretable, unless steps are taken to maintain blood levels of the other AEDs. A method of addressing this problem is illustrated in the case of an imidazole, R 57720. Adverse experiences may also occur more readily when a new drug is added to comedication than when it is given to normal volunteers and these problems in chronic trials can be anticipated from acute studies.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01243424
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  • 150
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    Comparative pharmacokinetics of ceftazidime in young, healthy and elderly, acutely ill males (1988)
    Springer
    European journal of clinical pharmacology 34 (1988), S. 179-186 
    Details
    ISSN: 1432-1041
    Keywords: ceftazidime ; pharmacokinetics ; elderly patients ; young volunteers ; acute infection
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of ceftazidime have been investigated after single and multiple i.v. doses in 9 young healthy male volunteers and 15 elderly male patients with acute bacterial infections. All subjects had normal, age-correlated glomerular function. Distribution and elimination in young volunteers were unaffected by posture and were similar to what has been reported earlier. In contrast, elderly patients had longer t1/2β (3.1 vs 1.9 h), larger AUC (414.0 vs 276.6 h·mg/l), lower total and renal clearances, reduced urinary recovery over 12 h and enlarged Vss. Total serum clearance of ceftazidime was closely correlated with the51Cr-EDTA clearance. There was no significant change in51Cr-EDTA clearance after seven days of treatment. A reduction in the dose of betalactam antibiotics eliminated by the kidney is advisable in elderly patients with an acute bacterial infection.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00614556
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  • 151
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    Pharmacokinetics and bioavailability of reduced and oxidized N-acetylcysteine (1988)
    Springer
    European journal of clinical pharmacology 34 (1988), S. 77-82 
    Details
    ISSN: 1432-1041
    Keywords: N-acetylcysteine ; pharmacokinetics ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics and bioavailability of N-acetylcysteine (NAC) have been determined after its intravenous and oral administration to 6 healthy volunteers. According to a randomized cross-over design each subject received NAC 200 mg i.v. and 400 mg p.o., and blood samples were collected for 30 h. Reduced NAC had a volume of distribution (VSS) of 0.59 l·kg−1 and a plasma clearance of 0.84 l·h−1·kg−1. The terminal half-life after intravenous administration was 1.95 h. The oral bioavailability was 4.0%. Based on total NAC concentration, its volume of distribution (VSS) was 0.47 l·kg−1 and its plasma clearance was 0.11 l·h−1·kg−1. The terminal half-life was 5.58 h after intravenous administration and 6.25 h after oral administration. Oral bioavailability of total NAC was 9.1%.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01061422
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  • 152
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    A preliminary study of the pharmacodynamics and pharmacokinetics of a novel enkephalin analogue [Tyr-D.Arg-Gly-Phe(4NO2)·Pro·NH2 (BW443C)] in healthy volunteers (1988)
    Springer
    European journal of clinical pharmacology 34 (1988), S. 67-71 
    Details
    ISSN: 1432-1041
    Keywords: BW443C ; enkephalin ; opioid peptide ; healthy volunteers ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have studied 16 healthy men to evaluate preliminary pharmacodynamics and kinetics of BW443C given by i.v. infusions. Four volunteers received escalating doses at weekly intervals, starting at 0.1 µg·kg−1 for 60 min and increasing to a maximum of 2.0 µg·kg−1·min−1 for 180 min. Subsequently 12 different subjects received single i.v. infusions of 10 µg·kg−1·min−1 for 20 min. Subjective effects were reported and objective measurements made of central nervous and cardiovascular effects. Blood was sampled at intervals on all occasions, plasma concentrations were determined by radioimmunoassay and pharmacokinetic profiles were analysed using NONLIN. Dry mouth and some nasal stuffiness were reported and postural hypotension occurred in 5/16 subjects at plasma concentrations 〉0.8 µg·ml−1. Supine blood pressure was well maintained in all subjects and hypotension resolved within 60–90 min of discontinuing the infusion. There was no evidence of sedation, mood change, nausea, vomiting, miosis, change in accomodation or respiratory depression. Rapid infusions produced transient feelings of warmth, heavy eyelids, heavy legs, and increased bowel sounds, which resolved despite increasing plasma concentrations. The disposition of the peptide was adequately described by a 2-compartment model with a mean ± SD plasma clearance of 123±18 ml·min−1 and a half-life of 2.0±0.4 h.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01061420
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  • 153
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    Pharmacokinetics of oxcarbazepine and 10-hydroxy-carbazepine in the newborn child of an oxcarbazepine-treated mother (1988)
    Springer
    European journal of clinical pharmacology 34 (1988), S. 311-313 
    Details
    ISSN: 1432-1041
    Keywords: oxcarbazepine ; newborns ; antiepileptic ; placental transfer ; 10-hydroxy-carbazepine ; pharmacokinetics ; breast milk transfer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Gaschromatography — mass spectrometry (GC/MS) was used to determine plasma levels of oxcarbazepine (OCB) and its main metabolite in a newborn girl and her OCB-treated mother during the first five post partum days. At delivery the maternal and neonatal plasma concentrations were in the same range, indicating considerable placental transfer of both substances. In spite of ingestion of both substances via breast milk, there was no accumulation in the baby. On the fifth post partum day OCB and 10-hydroxy-carbazepine (10-OH-CB) levels in plasma in the newborn were only 12 and 7%, respectively, of the values found on the first day after delivery.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00540963
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  • 154
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    The pharmacokinetics of doxifluridine and 5-fluorouracil after single intravenous infusions of doxifluridine to patients with colorectal cancer (1988)
    Springer
    European journal of clinical pharmacology 34 (1988), S. 439-443 
    Details
    ISSN: 1432-1041
    Keywords: doxifluridine ; colorectal carcinoma ; 5′-deoxy-5-fluorouridine ; 5-fluorouracil ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The disposition kinetics of a new 5-fluorouracil prodrug, 5′-deoxy-5-fluorouridine (5′dFUR, doxifluridine), were investigated in six patients with colorectal carcinoma. Each patient randomly received two single intravenous doses of 5′dFUR (2 and 4 g · m−2) on separate days. Plasma concentrations of 5′dFUR fell rapidly with terminal half-lives ranging from 16.1 to 27.7 min. A disproportionate increase in the area under the curve with increasing dose was seen in most patients. Doubling the dose resulted in a 40% decrease in nonrenal clearance (0.60 to 0.37 l · min−1) but no apparent change in renal clearance (0.32 to 0.29 l · min−1) or steady-state apparent volume of distribution (19.8 to 20.4 l). The mechanism for dose-dependence of 5′dFUR appears to be primarily due to nonlinear elimination associated with nonrenal processes rather than nonlinear plasma protein or tissue binding.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01046699
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  • 155
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    Kinetics and disposition of fluorescein-labelled liposomes in healthy human subjects (1988)
    Springer
    European journal of clinical pharmacology 34 (1988), S. 475-479 
    Details
    ISSN: 1432-1041
    Keywords: liposomes ; sodium fluorescin ; pharmacokinetics ; clinical studies ; drug delivery ; normals
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The in vivo kinetics and organ uptake of multilamellar liposomes have been studied in healthy volunteers. Sodium fluorescein-containing liposomes composed of equimolar amounts of egg phosphatidylocholine and cholesterol were injected into a peripheral vein in 4 healthy subjects. Blood samples collected from the femoral artery, hepatic vein and pulmonary artery, were analysed for liposomal dye content. The results, showing involvement of the reticuloendothelial system (RES) in the removal of liposomes, confirmed those previously obtained with radiolabelled preparations. Use of an innocuous liposomal marker (sodium fluorescein) and conventional vascular catheterization techniques, as employed here, may provide a reliable and clinically acceptable approach to establishing disease-induced changes in the kinetics of uptake of drug-containing liposomes by the RES, and thus help in the design of protocols for effective treatment.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01046705
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  • 156
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    Pharmacokinetics of xamoterol after intravenous and oral administration to volunteers (1988)
    Springer
    European journal of clinical pharmacology 34 (1988), S. 469-473 
    Details
    ISSN: 1432-1041
    Keywords: xamoterol ; cardiac failure ; beta1-adrenoceptor partial agonist ; pharmacokinetics ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of xamoterol, a β-adrenoceptor partial agonist under clinical evaluation for the treatment of mild to moderate heart failure, have been studied in 12 healthy male subjects. They received 14 mg i.v. and oral doses of 50 and 200 mg as a tablet and 200 mg as a solution in a 4 way cross-over design. After i.v. dosing the elimination half-life was 7.7 h, the total body clearance was 224 ml·min−1 and the volume of distribution at steady-state (Vss) was 48 l. Sixty-two percent of the dose was recovered unchanged in urine. After oral doses, the absolute bioavailability of xamoterol was shown to be 5% irrespective of whether the dose was administered as a tablet or solution. Peak plasma concentrations occurred at about 2 h for the tablet dose and slightly earlier (1.4 h) for the solution. Peak plasma concentration, AUC and urinary recovery of unchanged drug increased in proportion to dose. The apparent elimination half-life after oral doses (16 h) was significantly longer than that observed after an intravenous dose. Despite the low bioavailability, the degree of inter-subject variability of oral bioavailability was small probably indicating that the controlling factor is the hydrophilic nature of the molecule rather than extensive first pass metabolism or poor dissolution of xamoterol from the tablet formulation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01046704
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  • 157
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    The effects of posture on the pharmacokinetics of intramuscular benzylpenicillin (1988)
    Springer
    European journal of clinical pharmacology 33 (1988), S. 629-635 
    Details
    ISSN: 1432-1041
    Keywords: benzylpenicillin ; posture ; intramuscular administration ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Previous reports have produced conflicting results as to whether changes in posture affected the pharmacokinetics of the penicillins. We have studied the pharmacokinetics of intramuscularly administered benzylpenicillin in normal subjects during bedrest and ambulation and compared it with data obtained following intravenous administration of the same dose to the same subjects under the same conditions. The values of area under the curve, total clearance, mean residence time and renal clearance found during ambulation were 1175 (min·min·l−1), 488 (ml·min−1), 101 (min), and 264 (ml·min−1) (means). The corresponding values for bedrest were 1032 (min·mg·l−1), 544 (ml·min−1), 96.7 (min), and 315 (ml·min−1). There was a significant difference between the areas under the curve with change of posture but not between any of the other pharmacokinetic variables. The differences observed in this study are unlikely to be of clinical relevance. We suggest that the differences between the results of this study and those of previous studies may be related to the level of exercise undertaken by the subjects in the various studies.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00542500
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  • 158
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    The disposition of biphenylacetic acid following topical application (1988)
    Springer
    European journal of clinical pharmacology 33 (1988), S. 639-642 
    Details
    ISSN: 1432-1041
    Keywords: biphenylacetic acid ; plasma and synovial fluid concentrations ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Plasma and synovial fluid concentrations of biphenylacetic acid were determined following application of 3 g of 3% biphenylacetic acid gel to one knee of patients suffering from rheumatoid arthritis. The mean peak plasma concentration was 34 ng/ml. Synovial fluid concentrations tended to follow plasma concentrations but at a somewhat lower level, the mean peak synovial fluid concentration was 21 ng/ml. The average ratio of synovial fluid AUC (0–24 h) to plasma AUC (0–24 h) was 0.58, r=0.97. Where patients had bilateral effusions, the concentration in the ipsilateral knee at each time point examined was not significantly different to that in the contralateral knee, suggesting that absorption was initially into the plasma and subsequently into the synovium.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00542502
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  • 159
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    Pharmacokinetic and pharmacodynamic properties of a new controlled-release formulation of metoprolol: A comparison with conventional tablets (1988)
    Springer
    European journal of clinical pharmacology 33 (1988), S. S9 
    Details
    ISSN: 1432-1041
    Keywords: metoprolol ; controlled-release formulation ; pharmacokinetics ; pharmacodynamics ; exercise heart rate ; healthy volunteers ; efficacy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetic and pharmacodynamic properties of a new multiple-unit, controlled-release (CR) formulation of metoprolol1 (metoprolol succinate, 95 mg once daily), which has almost constant (zero-order) release properties over most of a 24-h dose interval, have been compared with those of conventional metoprolol tablets (metoprolol tartrate, 100 mg once daily and 50 mg twice daily), in 12 healthy male volunteers. The steady-state plasma concentrations of metoprolol after five days of treatment varied less throughout the day with the CR than with the conventional formulation. This was associated with a considerably lower peak plasma concentration and the achievement of a significantly higher plasma concentration at the end of the dose interval. Similarly, the effect on exercise-induced tachycardia was maintained at a relatively constant level throughout the day after treatment with the CR formulation. A significantly greater effect 24 h after administration was achieved with the CR formulation, when compared with once-daily dosing with metoprolol tablets, 100 mg. Twice-daily dosing with metoprolol tablets, 50 mg, produced a similar β1-blocking effect at the end of the dose interval to that observed with metoprolol CR. Although the steady-state plasma concentrations indicated significantly lower systemic availability for the CR formulation, compared with both regimens of metoprolol tablets, the total effect over the dose interval, expressed as the area under the efficacy curve (AUEC), was similar for the three treatments. The relationship between steady-state plasma concentrations and the pharmacodynamic efficacy at corresponding times, indicated that plasma concentrations were more effectively utilized after the administration of the CR formulation than after the conventional tablet regimens. The results of this study clearly indicate the potential benefits offered by the new metoprolol CR formulation, under all circumstances where a constant degree of β1-selective blockade, without plasma peaks and troughs, is preferred.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00578406
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  • 160
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    Influence of once-monthly rifampicin and daily clofazimine on the pharmacokinetics of dapsone in leprosy patients in Nigeria (1988)
    Springer
    European journal of clinical pharmacology 34 (1988), S. 73-76 
    Details
    ISSN: 1432-1041
    Keywords: dapsone ; rifampicin ; clofazimine ; leprosy ; drug interaction ; multidrug therapy ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In leprosy patients in Nigeria the influence of daily clofazimine and of once-monthly rifampicin on the pharmacokinetics of dapsone has been investigated. Three days after rifampicin the elimination half-life of dapsone was reduced from 40.4 to 25.3 h (n=23). Correspondingly, the plasma dapsone 24 h after the last dose had fallen significantly from 2.63 to 2.02 mg/l. Clofazimine did not cause change in the pharmacokinetics of dapsone. It was concluded that, although rifamipicin had a considerable influence on the pharmacokinetics of dapsone, there is no reason to adjust the dose of dapsone during multidrug therapy of leprosy.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01061421
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  • 161
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    Influence of digestive secretions and food on intestinal absorption of nicardipine (1988)
    Springer
    European journal of clinical pharmacology 34 (1988), S. 165-171 
    Details
    ISSN: 1432-1041
    Keywords: nicardipine ; pharmacokinetics ; gastrointestinal absorption ; influence of food ; intestinal perfusion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The role of digestive absorption in the pharmacokinetics of nicardipine has been studied by the perfusion technique. Nicardipine (40 mg) was perfused in six healthy subjects at 5 ml/min for 2 h either in isotonic saline with (Experiment A) or without (B) an occlusive balloon isolating the test segment from digestive secretions, or in a nutrient solution (Experiment C). In Experiments A and B, 100% of nicardipine was absorbed from the jejunal lumen in a 25 cm test segment and in Experiment C it was slightly lower (94%). There was no relationship between the absorption of nicardipine and water movement or bile salt concentration in the jejunum. Nicardipine was already present in the first plasma sample taken after 15 min and the peak level was found at the end of the perfusion. The areas under the curves differed widely between subjects, because of interindividual variation in the first pass effect, but they were similar in Experiments A, B and C. The experimental data showed a good fit to a mode involving a two-phase absorption process. The first phase was associated with intestinal perfusion (zero order process) and the second with passage accross the intestinal wall (1st order process). In three further healthy subjects, nicardipine in saline was perfused in the jejunum and then in the ileum on consecutive days. Mean plasma levels over time were similar. The study showed that absorption of nicardipine both from the jejunum and the ileum was complete and was especially rapid. The food-induced change in the kinetics of absorption from the jejunum was too small to affect the pharmacokinetic parameters of nicardipine.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00614554
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  • 162
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    Pharmacokinetics of nisoldipine in renal dysfunction (1988)
    Springer
    European journal of clinical pharmacology 34 (1988), S. 207-209 
    Details
    ISSN: 1432-1041
    Keywords: nisoldipine ; renal dysfunction ; pharmacokinetics ; blood pressure control
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of nisoldipine have been studied after oral administration of one 10 mg tablet to 3 groups of patients: Group A (n=8) with a mean creatinine of 90 ml/min, Group B (n=8) with a mean creatinine clearance of 12 ml/min and Group C of 12 patients on maintenance haemodialysis. All of them were studied off-dialysis and 7 were also studied on a dialysis day. No significant differences were observed between Groups A, B and C (on an interdialysis day) in AUC (0–7h), tmax, Cmax and plasma protein binding. Unchanged nisoldipine could not be recovered from the urine in any patient. Haemodialysis did not significantly affect AUC, tmax and Cmax, and nisoldipine could not be detected in the dialysate. The results indicate that the dose of nisoldipine need not be changed in patients with renal dysfunction, and that a supplementary dose is not required after haemodialysis. Blood pressure in the uraemics fell more than in the patients with good renal function.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00614560
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  • 163
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    Single- and multiple-dose pharmacokinetics of terodiline in geriatric patients (1988)
    Springer
    European journal of clinical pharmacology 34 (1988), S. 291-297 
    Details
    ISSN: 1432-1041
    Keywords: terodiline ; elderly patients ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary As a target group, geriataric patients were selected for pharmacokinetic studies with terodiline (Mictrol), an anticholinergic and calcium antagonist drug effective in the treatment of urinary incontinence. The single-dose kinetics in the geriatric patients (mean age 82 years) differed significantly from that previously found (Hallén et al. 1987) in healthy volunteers (mean age 35 years). There were higher peak serum concentrations (110 vs 79 µg·l−1), increased half-life (189 vs 60 h), lower renal clearance (4.0 vs 10.9 ml·min−1) and lower total clearance (29 vs 75 ml·min−1). Multiple-doses of 12.5 mg b.d. for 6–8 weeks resulted in a mean steady-state concentration of 642 µg·l−1, which was in agreement with the single dose parameters. The studied geriatric patients can be characterized not only as old, but also as frail, bedridden, having several diseases and polymedicated. The differences in pharmacokinetics between younger and elderly subjects can be attributed to a variety of complex factors, which may alter the clearance and/or the volume of distribution.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00540958
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  • 164
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    The influence of cholestyramine on the elimination of tenoxicam and piroxicam (1988)
    Springer
    European journal of clinical pharmacology 34 (1988), S. 283-289 
    Details
    ISSN: 1432-1041
    Keywords: piroxicam ; tenoxicam ; cholestyramine ; accelerated drug elimination ; pharmacokinetics ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have studied the influence of multiple oral doses of cholestyramine on the single dose pharmacokinetics of tenoxicam and piroxicam in eight healthy young volunteers. Each subject received on two occasions single intravenous injections of 20 mg tenoxicam and on another two occasions single oral doses of 20 mg piroxicam. Both medications were followed by multiple oral doses of either cholestyramine or plain water (placebo). Compared with placebo cholestyramine accelerated the elimination of both drugs. The average values of half-lives were reduced (tenoxicam: 31.9 h vs 67.4 h; piroxicam: 28.1 h vs 46.8 h) due to increases in clearance. Cholestyramine-mediated enhancement of drug elimination was most pronounced in the subjects with a comparatively low baseline drug clearance. Thus, intersubject variability in clearance was smaller when the drug administrations were followed by the anion-exchange resin. The twofold acceleration of tenoxicam elimination in the present study in man contrasts with a much larger effect (five-fold) seen in experiments with dogs. This points to a much easier access of unchanged tenoxicam to the intestinal lumen in the dogs than in man. Comparing the pharmacokinetics of tenoxicam and piroxicam in the same volunteers revealed a high degree of correlation in clearance and half-lives and similar intersubject variabilities in mean kinetic variables.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00540957
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  • 165
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    The pharmacokinetics of olsalazine sodium in healthy volunteers after a single i.v. dose and after oral doses with and without food (1988)
    Springer
    European journal of clinical pharmacology 34 (1988), S. 481-488 
    Details
    ISSN: 1432-1041
    Keywords: olsalazine sodium ; 5-ASA ; ac-5-ASA ; pharmacokinetics ; effect of food
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Olsalazine sodium (5,5′-azodisalicylic acid (OLZ)) was given to eight healthy volunteers as a 10 mg i.v. bolus dose and as a 1 g oral dose with and without food. To five fasting participants single oral doses of 2 g and 4 g were given. Blood and urine were collected during three weeks after each dose and were assayed for OLZ, a conjugate identified as a sulphate of OLZ (OLZs), 5-aminosalicylic acid (5-ASA), and N-acetyl-5-aminosalicylic acid (ac-5-ASA). The study showed that: 1. OLZ had a very short elimination half-life, mean 56 min. 2. OLZ was absorbed from the intestinal tract to a very small extent, as seen from the low systemic availability and low urinary excretion, 2.3% and 0.31% respectively, for a 1 g dose taken fasting. 3. OLZ was present in the serum partly as a conjugate, which was identified as an O-sulphate. Following the i.v. dose the serum half-life of the O-sulphate was estimated to be 7 days. 4. Food intake did not influence the systemic availability of OLZ and ac-5-ASA. 5. There was no dose-dependent increase of OLZ absorption with single doses up to 2 g, but a 4-g dose showed a more than two-fold increase in the individual peak serum concentration and in the systemic availability of OLZ. However, there was no significant increase in the mean residence time (MRT) for OLZ or in the serum concentration of either 5-ASA or ac-5-ASA at a dose of 4 g.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01046706
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  • 166
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    CSF and plasma pharmacokinetics of pethidine and norpethidine in man after epidural and intrathecal administration of pethidine (1988)
    Springer
    European journal of clinical pharmacology 34 (1988), S. 625-631 
    Details
    ISSN: 1432-1041
    Keywords: pethidine ; analgesics ; epidural-/intrathecal injection ; pharmacokinetics ; drug metabolism ; norpethidine ; adverse effects ; CSF drug levels
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The disposition of pethidine and its main metabolite, norpethidine, in cerebrospinal fluid (CSF) and plasma was studied in 11 thoracic surgery patients after lumbar epidural (100 mg;n=6) or lumbar intrathecal (25 mg;n=5) administration of pethidine. Pethidine appeared more slowly in plasma after intrathecal than after epidural administration (tmax 2.3 h and 14 min, respectively), but systemic bioavailability was similar. The CSF concentrations of pethidine were higher than those in plasma after both routes of administration. The maximal CSF/plasma concentration ratio was 6000 to 45000 after intrathecal administration but was only 26 to 97 after the epidural route. Pethidine was rapidly distributed in CSF; nine to ten h after the intrathecal and epidural injections the CSF/plasma concentration ratios were 12 to 89 and 2 to 33, respectively. The calculated bioavailability in CSF of epidural pethidine was 10.3%. The terminal elimination half-life of pethidine was 6.0 h (CSF) and 5.4 h (plasma) after intrathecal administration and 8.6 h (CSF) and 8.8 h (plasma) after epidural injection. The volume of distribution of unchanged pethidine in the subarachnoid space was 13 ml·kg−1 and clearance from the CSF was 15 µl·kg−1·min−1. In all patients receiving intrathecal pethidine and in some patients after epidural pethidine, CSF norpethidine concentrations were higher than those in plasma; the maximum CSF norpethidine was 102 to 1211 ng·ml−1 and 14 to 210 ng·ml−1 and the maximum CSF/plasma norpethidine concentration ratios were 21 to 652 and 0.6 to 14 times after intrathecal and epidural administration, respectively. Norpethidine was rapidly distributed and its level in CSF was about the same or lower than in plasma during the terminal elimination phase. The maximum CSF norpethidine level was 1.2±1.0% of that of pethidine after intrathecal injection. Thus, epidural pethidine enters the CSF more rapidly and to a greater extent than has been previously shown for epidural morphine, but pethidine is more rapidly redistributed from CSF. The terminal elimination half-life of pethidine was found to be long in relation to the reported duration of analgesia after a single spinal dose of pethidine, which suggests a potential risk of accumulation within the CSF on multiple spinal injections of pethidine. Pethidine is partly metabolised within the subarachnoid space by N-dealkylating enzymes in the CNS. After intrathecal injection of more than 25 mg pethidine, the concentration of the principle metabolite, norpethidine, in CSF may be higher than that associated with CNS toxicity in man.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00615228
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  • 167
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    Doxazosin in patients with hypertension (1988)
    Springer
    European journal of clinical pharmacology 35 (1988), S. 21-24 
    Details
    ISSN: 1432-1041
    Keywords: doxazosin ; hypertension ; alpha-adrenergic blockade ; bioavailability ; pharmacokinetics ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The antihypertensive effects and steady-state pharmacokinetics of doxazosin, as well as the bioequivalence of four dosage forms, were studied in 25 hypertensive patients. For an 8 mg daily dose mean Cmax at steady-state for all patients was 108 ng/ml; the mean tmax was 1.8 h. The mean terminal elimination half-life was 22 h. The four tablets containing 1, 2, 4, or 8 mg of doxazosin were bioequivalent in delivering the 8 mg dose. In patients with mild to moderate hypertension, 26-day treatment with doxazosin resulted in blood pressure reduction of 10/7 mm Hg in the supine and 13/18 mm Hg in the standing position. Adverse effects were generally mild and of brief duration.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00555502
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  • 168
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    The absolute systemic availability of a new oral formulation of co-dergocrine in healthy subjects (1988)
    Springer
    European journal of clinical pharmacology 35 (1988), S. 53-57 
    Details
    ISSN: 1432-1041
    Keywords: codergocrine ; prolactin ; hydergine ; pharmacokinetics ; systemic availability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have studied the absolute systemic availability (f) of an oral formulation (Hydergin spezial = Hydergine FASR 4 mg per tablet) of codergocrine by three different methods. Twelve healthy volunteers received single doses of 0.9 mg co-dergocrine intravenously and 8.0 mg orally in a randomized crossover design. The pharmacological effect of co-dergocrine was monitored as a reduction in plasma prolactin. Maximal plasma concentrations of co-dergocrine after oral dosing ranged between 0.181 and 1.307 ng·ml−1. Maximal urinary excretion ranged between 4.7 and 9.9 µg·h−1 and between 0.3 and 2.3 µg·h−1 after intravenous and oral doses respectively. Clearance was measured as 90±22 l·h−1 and the absolute systemic availability (f) as 2.25±0.65% by using the areas under the plasma concentration-time curves extrapolated to infinity. Calculation of f by comparing areas up to 32 h or the fractions of the dose excreted in urine led to identical results. The intravenous and oral doses produced similar pharmacological effects (reduction of plasma prolactin concentrations) despite the small value of f.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00555507
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  • 169
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    Lack of effect of cimetidine on the pharmacokinetics and metabolism of a single oral dose of metronidazole (1988)
    Springer
    European journal of clinical pharmacology 35 (1988), S. 65-68 
    Details
    ISSN: 1432-1041
    Keywords: metronidazole ; cimetidine ; pharmacokinetics ; drug interaction ; drug metabolism ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The time course of the effect of cimetidine on the pharmacokinetics of metronidazole was investigated in 6 healthy volunteers. Cimetidine 1.0 g/day was administered for 9-days and metronidazole 500 mg was administered orally on the second and eighth days, and in a control experiment. During cimetidine treatment the plasma kinetics of metronidazole and its partial clearance by renal excretion of the unchanged compound, glucuronidation, hydroxylation and oxidation to its acetic acid metabolite were not significantly different from the control values. The results indicate that cimetidine does not influence the pharmacokinetics or metabolism of a single oral dose of metronidazole.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00555509
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  • 170
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    Pharmacokinetics of bolus intravenous and oral doses of L-carnitine in healthy subjects (1988)
    Springer
    European journal of clinical pharmacology 35 (1988), S. 69-75 
    Details
    ISSN: 1432-1041
    Keywords: L-carnitine ; pharmacokinetics ; intravenous and oral doses ; bioavailability ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of single intravenous and oral doses of L-carnitine 2 and 6 g was studied in 6 healthy subjects on a low-carnitine diet. Carnitine was more rapidly eliminated from plasma after the 6 g dose. Comparing the doses, the t1/2β of the elimination phase (β) was 6.5 h vs 3.9 h, the elimination constant 0.40 vs 0.50 h−1 and the plasma carnitine clearance was 5.4 vs 6.11 · h−1 for the 2 g and 6 g doses, respectively, showing dose-related elimination. Saturable kinetics were not found. The apparent volumes of distribution after the two doses were not significantly different and were of the same order as the total body water. Urinary recoveries of the 2 g and 6 g doses were 70% and 82%, respectively, during the first 24 h. Following the oral doses, there was no significant difference between the areas under the plasma carnitine concentration-time curves. Urinary recovery was 8% and 4% for the 2 g and 6 g doses during the first 24 h. Oral bioavailability was 16% for the 2 g dose and 5% for the 6 g dose. The results suggest that the mucosal absorption of carnitine was already saturated by the 2 g dose.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00555510
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  • 171
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    Therapeutic doses of codeine have no effect on acetaminophen clearance or metabolism (1988)
    Springer
    European journal of clinical pharmacology 35 (1988), S. 109-111 
    Details
    ISSN: 1432-1041
    Keywords: acetaminophen ; codeine ; clearance ; metabolite formation ; glucuronidation ; pharmacokinetics ; healthy volunteers ; drug interaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In nine healthy volunteers, the clearance and metabolism of acetaminophen 1000 mg i.v. was evaluated with and without two concomitant oral doses of codeine in order to investigate a possible interaction. Plasma acetaminophen was followed for 720 min and urine was collected for 24 h after each dose for determination of metabolites. When codeine was coadministered, the average total clearance of acetaminophen and its clearance by glucuronidation, sulphation and mercapturate formation were 0.58 to 1.12-times the control values. It is concluded that therapeutic doses of codeine do not influence the clearance or metabolism of acetaminophen.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00555519
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  • 172
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    The effect of hydralazine on steady-state plasma concentrations of metoprolol in pregnant hypertensive women (1988)
    Springer
    European journal of clinical pharmacology 35 (1988), S. 131-135 
    Details
    ISSN: 1432-1041
    Keywords: metoprolol ; hydralazine ; hypertension ; pregnancy ; pharmacokinetics ; drug interactions
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have studied the plasma concentrations levels of metoprolol after its twice daily administration in a dose of 50 mg for 4 days in ten, hypertensive pregnant women to the during monotherapy and in combination with 25 mg of hydralazine given twice daily. Hydralazine increased the median AUC and Cmax of metoprolol by 38% and 88% respectively, and decreased the tmax from 1.5 h to 1.0 h. Hydralazine had no effect on the plasma concentrations of alpha-OH-metoprolol. These results suggest that the effect of hydralazine on metoprolol plasma concentrations is primarily due to a reduction in first-pass elimination.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00609241
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  • 173
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    Pharmacokinetics of xamoterol after intravenous and oral administration to patients with chronic heart failure (1988)
    Springer
    European journal of clinical pharmacology 35 (1988), S. 183-185 
    Details
    ISSN: 1432-1041
    Keywords: xamoterol ; cardiac failure ; beta1-adrenoceptor partial agonist ; pharmacokinetics ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of xamoterol, a β-adrenergic partial agonist under clinical evaluation for the treatment of mild to moderate heart failure, have been studied in 8 cardiac failure patients (NYHA Class II) of mean age 62 years. After i.v. dosing, the elimination half-life was 7.4±0.4 h, the total body clearance was 228±30 ml·min−1 and the volume of distribution at steady-state was 56±91. 72.5±4.3% of the dose was recovered unchanged in urine. After the oral dose, the absolute bioavailability of xamoterol was shown to be 5.9%. Peak plasma concentrations occurred 1 to 2.5 h after the oral dose. The apparent elimination half-life was significantly longer after oral doses (16±2 h) compared to that observed after an intravenous dose. Renal clearance of xamoterol exceeded glomerular filtration rate as measured by creatinine clearance. The pharmacokinetics of xamoterol in cardiac failure patients with good renal function (creatinine clearance 〉90 ml·min−1) were similar to published data in young healthy male volunteers.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00609250
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  • 174
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    Intra- and inter-subject variation in the pharmacokinetics of indoramin and its 6-hydroxylated metabolite (1988)
    Springer
    European journal of clinical pharmacology 35 (1988), S. 195-198 
    Details
    ISSN: 1432-1041
    Keywords: indoramin ; 6-hydroxyindoramin ; pharmacokinetics ; concentration variability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Intra- and inter-subject variation in the kinetics of indoramin and its active metabolite 6-hydroxyindoramin have been studied in 5 young, healthy, male volunteers administered a single oral dose of the drug on 5 separate occasions. Inter-subject variation represented the main source of variability in indoramin plasma concentrations with, for example, the between-subjects sum of squares (a measure of the contribution to the total variability) representing around 97% of the total sum of squares for Cmax and AUC (0–24). Intra-subject and inter-subject coefficients of variation (C.V.s) were circa 20% and 100% respectively for both these parameters. Variability in 6-hydroxyindoramin concentrations was much lower and was approximately equally derived from intra- and inter-subject variation, with the C.V.s being approximately 44% for both Cmax and AUC (0–24). The results imply that the kinetic behaviour of indoramin within an individual will prove relatively consistent, despite widespread inter-subject variation, once an appropriate dosage regime has been established.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00609252
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  • 175
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    The pharmacokinetics of ceftazidime in patients with impaired renal function and concurrent frusemide therapy (1988)
    Springer
    European journal of clinical pharmacology 35 (1988), S. 273-279 
    Details
    ISSN: 1432-1041
    Keywords: ceftazidime ; frusemide ; pharmacokinetics ; renal insufficiency
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have studied the pharmacokinetics of ceftazidime in 37 patients suffering from serious bacterial infections. All the patients had impairment of renal function and received moderate to high doses of frusemide concurrently. The doses of ceftazidime were given according to renal function as recommended by the manufacturer. Serum and urine samples were frequently collected, and drug concentrations measured by high performance liquid chromatography. The patients were grouped and evaluated according to renal function, mean (SD) creatinine clearances ranging from 70.1 (12.4) to 11.0 (3.2) ml·min−1. The pharmacokinetics of ceftazidime depended on renal function. A statistically significant increase in ceftazidime elimination half-life and decreases in urinary recovery, total body clearance, and renal clearance in proportion to the decrease in renal function were observed (p〈0.05). The apparent volume of distribution also increased, but not significantly (p〉0.05). A linear correlation was found between the total body and renal clearances of ceftazidime and creatinine clearance. The extrarenal clearance increased from 3.9 to 14.0 ml·min−1 with decreasing renal function. Concurrent treatment with ceftazidime and moderate to high doses of frusemide did not impair renal function and no evidence of nephrotoxicity was found.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00558265
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  • 176
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    Electronic Resource
    Does alpha1-acid glycoprotein reduce the unbound metabolic clearance of disopyramide in patients with renal impairment? (1988)
    Springer
    European journal of clinical pharmacology 35 (1988), S. 313-317 
    Details
    ISSN: 1432-1041
    Keywords: disopyramide ; alpha1-acid glycoprotein ; renal dysfunction ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of disopyramide was studied in 15 patients with renal dysfunction (4 with pyelonephritis, 7 with glomerular nephritis and 4 with interstitial nephritis). The elimination rate constant of unbound disopyramide was 0.094 h−1 and CLu/f (unbound clearance divided by bioavailability) was 245 ml/min. Both the unbound renal clearance (CLR) and CLu/f were highly correlated with the creatinine clearance (CLCR). The apparent unbound metabolic clearance in the patients was approximately two-fold lower than that previously reported in normal subjects. The estimated unbound metabolic clearance in the renal dysfunction patients showed a significant negative correlation with the α1-acid glycoprotein (AAG) concentration and only a weak, non-significant correlation with CLCR. As AAG in the renal dysfunction subjects was increased in comparison with normal values, it is possible that AAG is a factor in the decrease in the apparent unbound metabolic clearance.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00558271
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  • 177
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    Electronic Resource
    The pharmacokinetics of theophylline and enprofylline in patients with liver cirrhosis and in patients with chronic renal disease (1988)
    Springer
    European journal of clinical pharmacology 35 (1988), S. 357-362 
    Details
    ISSN: 1432-1041
    Keywords: theophylline ; enprofylline ; liver cirrhosis ; renal failure ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have studied the pharmacokinetics of theophylline and enprofylline in patients with liver cirrhosis, patients with chronic renal failure, and healthy subjects, and have assessed the predictive value of routine tests of liver function and renal function (creatinine clearance) for theophylline and enprofylline total body clearances. Theophylline clearance was significantly decreased in the patients with liver cirrhosis compared with both the patients with renal failure and the healthy subjects (the mean values in the three groups were 24, 47, and 46 ml·h−1·kg−1 respectively. Enprofylline clearance was significantly decreased in the patients with chronic renal failure, compared with both the patients with liver cirrhosis and the healthy subjects (the values in the three groups were 64, 250, and 289 ml·h−1·kg−1 respectively. There was a strong correlation between creatinine clearance and enprofylline clearance, while there was only a poor correlation between the liver function tests and theophylline clearance. It appears that in various clinical situations enprofylline elimination can be predicted more precisely than theophylline elimination, which may make the drug safer in clinical practice.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00561364
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  • 178
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    The behaviorally active peptide ACTH 4-10: Measurement in plasma and pharmacokinetics in man (1988)
    Springer
    European journal of clinical pharmacology 35 (1988), S. 371-377 
    Details
    ISSN: 1432-1041
    Keywords: ACTH 4-10 ; radioimmunoassay ; plasma extraction ; pharmacokinetics ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A specific radioimmunoassay for the quantitative measurement of ACTH 4-10 and a procedure for its extraction from plasma have been developed. Its pharmacokinetics was studied in eight healthy male volunteers given ACTH 4-10 125 µg/kg body weight as a bolus i.v. injection, by infusion and intranasally. Following the i.v. bolus, plasma levels rapidly declined biexponentially, with half-lives of 0.39±0.05 min for the α-phase and 3.84 ± 1.5 min for the β-phase (mean±SD). The constant rate i.v. infusion yielded steady-state levels between 0.74 and 5.06 ng/ml plasma. Administered as intranasal spray, absorption of intact ACTH 4-10 was low and variable (maximal bioavailability 7.6%). The results are discussed in relation to the dose-dependent effects of ACTH 4-10 on the auditory evoked potential.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00561367
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  • 179
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    The pharmacokinetics of bendazac-lysine and 5-hydroxybendazac, its main metabolite, in patients with hepatic cirrhosis (1988)
    Springer
    European journal of clinical pharmacology 35 (1988), S. 391-396 
    Details
    ISSN: 1432-1041
    Keywords: bendazac ; liver cirrhosis ; pharmacokinetics ; drug metabolism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have studied the pharmacokinetics of bendazac and its major metabolite, 5-hydroxybendazac, in 11 patients with hepatic cirrhosis after the oral administration of a single 500 mg tablet of bendazac-lysine, and compared them with those obtained from 10 healthy adults. The rate of absorption of bendazac, as assessed by tmax and Cmax, is similar in patients and in healthy subjects. The drug is eliminated mostly by metabolism in healthy adults, more than 60% of the dose being excreted in the urine as 5-hydroxybendazac and its glucuronide. Hepatic insufficiency impairs this metabolism, a two-fold decrease in apparent plasma clearance (CL/f) being observed in the patients. Although the plasma unbound fraction of bendazac is increased in patients (the drug is highly bound to plasma albumin), the apparent volume of distribution (V/f) is unchanged. In consequence, the half-life of bendazac is increased two-fold in the patients. Impairment of metabolism decreases the formation of 5-hydroxybendazac, but metabolism remains the main route of its elimination. Renal excretion of bendazac accounts for about 10% of the dose in both patients with cirrhosis and healthy subjects. We conclude that in patients with severe hepatic insufficiency the daily dose of bendazac-lysine should be havled.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00561370
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  • 180
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    Pharmacokinetics of ketorolac tromethamine in humans after intravenous, intramuscular and oral administration (1988)
    Springer
    European journal of clinical pharmacology 35 (1988), S. 423-425 
    Details
    ISSN: 1432-1041
    Keywords: ketorolac tromethamine ; non-narcotic analgesic ; pharmacokinetics ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of ketorolac tromethamine, a potent non-narcotic analgesic agent used for relief of moderate to severe pain, has been studied in 15 healthy volunteers who received single 10 mg doses intravenously (i.v.), intramuscularly (i.m.) and orally (p.o.) in a three-way cross-over design. The kinetics of i.v. ketorolac were characterized by a terminal half-life of 5.09 h, a small plasma clearance (CL = 0.35 ml·min−1·kg−1) and a small tissue distribution (Vss=0.111·kg−1, Vβ=0.17 l·kg−1; mean (SD). Following i.m. and p.o. administration, peak levels of approximately 0.8 µg/ml were rapidly attained (tmax = 0.8 and 0.9 h, respectively) and the systemic bioavailability was essentially complete.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00561376
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  • 181
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    Pharmacokinetics of ranitidine in patients undergoing haemofiltration (1988)
    Springer
    European journal of clinical pharmacology 35 (1988), S. 427-430 
    Details
    ISSN: 1432-1041
    Keywords: ranitidine ; haemofiltration ; renal failure ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of ranitidine was investigated in 11 patients with acute or end stage renal failure during haemofiltration. Each patient received 50 mg ranitidine i.v. The mean distribution and elimination half lives were 0.13 and 2.57 h, respectively. The total body clearance (CL) and volume of distribution (Vz) were 298 ml·min−1 (5.19 ml·min−1·kg−1) and 1.081·kg−1, respectively. About 17.1% of the administered dose was removed by haemofiltration (in approximately 201 filtrate). Five of the patients still had some urine output and they excreted 0.1 to 11.8% of the dose in urine in 24 h. The haemofiltration clearance was 66.9 ml·min−1 at a filtrate flow rate of 86 ml·min−1, corresponding to a mean sieving coefficient of 0.78 (n=6). As plasma concentrations were still in an effective range after haemofiltration, dose supplementation is not recommended.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00561377
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  • 182
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    Electronic Resource
    Pharmacokinetics of a new sublingual formulation of temazepam (1988)
    Springer
    European journal of clinical pharmacology 35 (1988), S. 437-439 
    Details
    ISSN: 1432-1041
    Keywords: temazepam ; formulations ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of a new 10 mg sublingual tablet formulation of temazepam and those of a currently marketed 10 mg oral capsule formulation were evaluated in a group of ten healthy volunteers. No significant differences were observed between the two formulations with respect to any of the pharmacokinetic parameters assessed. Lethargy and somnolence were reported on both capsule and tablet by several subjects at a time which corresponded with the maximum concentration of drug in plasma. The data indicate that the sublingual tablet and orally administered capsule have a similar pharmacokinetic and pharmacodynamic profile.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00561380
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  • 183
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    Pharmacokinetics of streptomycin in Ethiopian children with tuberculosis and of different nutritional status (1988)
    Springer
    European journal of clinical pharmacology 33 (1988), S. 647-649 
    Details
    ISSN: 1432-1041
    Keywords: streptomycin ; tuberculosis ; malnutrition ; pharmacokinetics ; children
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Fifty-six malnourished Ethiopian children with tuberculosis classified in four nutrional groups (normal, underweight, marasmus and kwashiorkor), were given streptomycin 20 or 30 mg·kg−1 i.m. The plasma concentration-time data revealed an increased apparent volume of distribution in children with kwashiorkor compared to normals. The total plasma clearance was low and did not differ between the nutrional groups. Thus, the half-life was prolonged only in kwashiorkor. The results could be explained by decreased protein binding in plasma and decreased renal clearance by glomerular filtration.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00542504
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  • 184
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    Design of a new multiple-unit controlled-release formulation of metoprolol — Metoprolol CR (1988)
    Springer
    European journal of clinical pharmacology 33 (1988), S. S3 
    Details
    ISSN: 1432-1041
    Keywords: metoprolol ; controlled-release formulation ; pharmacokinetics ; plasma concentration profile
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A new controlled-release (CR) formulation of the β1-selective adrenoceptor antagonist metoprolol1 has been developed, aiming at an even 24-h pharmacological effect. In order to achieve this, using a once-daily dose, factors such as absorption characteristics, physicochemical properties, and technological aspects had to be considered. The new formulation, called metoprolol CR, is a disintegrating tablet consisting of several hundred coated pellets of metoprolol succinate, each pellet being its own CR delivery unit. In vitro testing and in vivo studies in healthy volunteers show that the new CR formulation gives continuous delivery of metoprolol throughout the day, resulting in smooth plasma concentration profiles, without peaks and troughs. The release of the drug is independent of pH and other physiological variables, such as food intake, which do not seem to alter the biopharmaceutical properties of the formulation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00578405
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  • 185
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    Pharmacokinetics of lisinopril in hypertensive patients with normal and impaired renal function (1988)
    Springer
    European journal of clinical pharmacology 34 (1988), S. 61-65 
    Details
    ISSN: 1432-1041
    Keywords: lisinopril ; renal failure ; half-life ; drug dose ; pharmacokinetics ; hypertension
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of lisinopril was studied after administration of single and multiple doses of 5 mg to hypertensive patients with normal and impaired renal function. In patients with severe renal failure the peak concentrations were higher, the decline in serum concentration was slower and the time to peak concentration was extended. Accumulation of lisinopril was highly correlated with the creatinine clearance. The effective half-life was doubled and tripled in patients with mild and severe renal impairment, respectively, as compared to patients with a normal renal function. Lisinopril lowered blood pressure in all three groups over 24 h. It is suggested that smaller doses of lisinopril should be administered to patients with severe renal failure.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01061419
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  • 186
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    Electronic Resource
    Single-dose and multiple-dose pharmacokinetics of etintidine in healthy volunteers (1988)
    Springer
    European journal of clinical pharmacology 34 (1988), S. 101-104 
    Details
    ISSN: 1432-1041
    Keywords: etintidine ; pharmacokinetics ; single-dose ; multiple-dose
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The present study was designed to determine the single- and multiple-dose pharmacokinetic profiles of the H2 receptor antagonist etintidine in healthy volunteers. Etintidine was rapidly absorbed and eliminated after the oral administration of 300 mg base equivalent of etintidine HCl in a capsule formulation to 11 healthy subjects. Comparison of the pharmacokinetics after a single dose and during steady state showed no significant differences (p〉0.05) in the mean values of Cmax, tmax, oral clearance, elimination rate constant, and renal clearance, indicating no significant accumulation of etintidine and no apparent time-dependent changes in the pharmacokinetics of etintidine during multiple dose administration.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01061428
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  • 187
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    Influence of food on the pharmacokinetics of dipyrone (1988)
    Springer
    European journal of clinical pharmacology 34 (1988), S. 105-107 
    Details
    ISSN: 1432-1041
    Keywords: dipyrone ; methylaminoantipyrine ; food interaction ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Twelve healthy volunteers were given a single oral dose of dipyrone 1 g, once while fasting and once after a standard breakfast. Plasma levels of the active dipyrone metabolite — Methylaminoantipyrine (MAA) were measured and the calculated pharmacokinetic parameters were compared. Taking dipyrone with food resulted in a small delay in the mean time to peak from 1.5 h to 1.9 h (p〈0.01). However, there was no significant difference in AUC, Cmax or Kelim between fasting and nonfasting conditions. The rate of absorption, expressed as the mean Kabs, was somewhat slower in the nonfasting state, but not significantly so. It is suggested that dipyrone may be taken regardless of the times of eating.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01061429
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  • 188
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    A double-blind and cross-over comparison of once daily doxazosin and placebo with steady-state pharmacokinetics in elderly hypertensive patients (1988)
    Springer
    European journal of clinical pharmacology 34 (1988), S. 119-123 
    Details
    ISSN: 1432-1041
    Keywords: doxazosin ; hypertension ; alpha1-adrenoceptor inhibitor ; elderly patients ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The α1-adrenoceptor antagonist doxazosin has been compared with placebo in 40 elderly hypertensive patients (mean age 71.4 years). At the end of 10 weeks once daily treatment with doxazosin the mean 24-h post-dose changes in standing and supine blood pressure compared with placebo were −6.9/−5.6 mmHg (systolic/diastolic) and −6.2/−5.5 mmHg respectively. The reductions in standing and supine diastolic blood pressures were statistically significant compared with placebo. At the end of treatment steady-state pharmacokinetics were evaluated in 18 patients. The plasma elimination half-life during the dose interval in these patients was 16.1 h (range 10.1–27.1 h) and the median time to peak plasma concentration was 3 h (range 1–4 h). One patient was withdrawn because of adverse effects (headache, weakness, and sweating) during doxazosin treatment. Once daily doxazosin reduced diastolic blood pressure and was well tolerated in these elderly hypertensive patients.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00614546
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  • 189
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    Effect of probenecid on the elimination and protein binding of ceftriaxone (1988)
    Springer
    European journal of clinical pharmacology 34 (1988), S. 151-156 
    Details
    ISSN: 1432-1041
    Keywords: ceftriaxone ; probenecid ; drug interaction ; protein binding ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The kinetics and binding parameters of ceftriaxone have been characterized in eight normal subjects who received, in sequence, 1.0 g ceftriaxone and 1.0 g ceftriaxone together with 250 and 500 mg probenecid q.i.d. Probenecid increased the total systemic clearance (CL S T ) from 0.244 to 0.312 ml/min/kg, whereas the terminal half-life (t 1/2(β) T ) fell from 8.1 to 6.5 h. In contrast, the renal clearance of free ceftriaxone (CL R F ) was decreased from 2.09 to 1.67 ml/min/kg, confirming a small but significant contribution of tubular secretion to the renal elimination of ceftriaxone. The final value of CL R F was attained with the lower dose probenecid, whereas the non-renal clearance of free ceftriaxone (CL NR F ) fell progressively from 2.78 to 1.90 ml/min/kg with the increasing probenecid dose. The total decrease in the systemic clearance of free ceftriaxone (CL S F ) after the higher dose of probenecid was about 30% (4.87 to 3.57 ml/min/kg). As a consequence of a decreased affinity constant (KA), the average free fraction in plasma (f) was increased by 54% after the low dose and by 74% after the high dose of probenecid. The protein binding interaction between probenecid and ceftriaxone appears to be unique. The results are of limited clinical consequence for ceftriaxone but they emphasise the importance of evaluating the kinetics of the free drug when examining interactions involving probenecid.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00614552
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  • 190
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    Influence of age on the pharmacokinetics of ceftazidime in acutely ill, adult patients (1988)
    Springer
    European journal of clinical pharmacology 34 (1988), S. 173-178 
    Details
    ISSN: 1432-1041
    Keywords: ceftazidime ; pharmacokinetics ; age dependency ; elderly patients ; acute infection
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The single and multiple i.v. dose pharmacokinetics of ceftazidime were investigated in 37 acutely ill patients with normal age-related glomerular function. Distribution was rapid with similar t1/2a at all ages. Compared to the younger patients, elderly subjects had lower total and renal clearances and reduced urinary recovery. Ceftazidime clearance was closely correlated with glomerular function. The t1/2β was approximately 2 h in young and middle-aged patients, 2.73 h in patients aged 60–79 years, and 3.54 h in those above 80 years. The AUC was more than doubled in the oldest patients compared to individuals younger than 40 years. Vss did not change with advancing age, but was larger than previously reported in healthy volunteers. Elimination variables were not altered during multiple dosing, but a small but significant increase in AUC was detected in the elderly. Dose reduction by 50% in patients more than 70 years old is suggested.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00614555
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  • 191
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    Pharmacokinetics and pharmacodynamics of propafenone during acute and chronic administration (1988)
    Springer
    European journal of clinical pharmacology 34 (1988), S. 187-194 
    Details
    ISSN: 1432-1041
    Keywords: propafenone ; 5-OH-propafenone ; antiarrhythmic effect ; pharmacokinetics ; chronic treatment
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of propafenone and 5-OH-propafenone and their relationship with the antiarrhythmic action and side effects have been studied in 10 patients with stable, frequent, premature ventricular beats (224–928 premature ventricular complexes/h). Observations were made after a single dose of propafenone 300 mg p.o., and after 1 and 3 months (only 5 out of 10 patients) of therapy with 300 mg t.d.s. After 1 month of treatment the plasma elimination half-life of propafenone (6.7 h) was almost twice as long as after a single dose (3.5 h), and the area under the plasma propafenone concentration-time curve (7620 ng·ml−1·h) was significantly larger than after single dose (3522 ng·ml−1·h); this was also true for the metabolite. The ratio of the AUCs of 5-OH-propafenone and propafenone decreased from the single dose (0.63) to 1 month (0.32). These variables remained stable up to 3 months. Eight patients had ≧75% reduction of premature ventricular complexes after 3 days of therapy, and in 7 they were completely suppressed; the response was maintained over 1 to 3 months. Side effects were minor and in no case had the drug to be withdrawn or the dose reduced. Thus, the kinetics of propafenone were time-dependent. Its active metabolite did not accumulate greatly during chronic treatment. The lasting antiarrhythmic effect observed in some patients suggests a b.d.s. regimen instead of t.d.s. dosing in selected patients.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00614557
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  • 192
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    Pharmacokinetics and safety of l-carnitine infused i. v. in healthy subjects (1988)
    Springer
    European journal of clinical pharmacology 34 (1988), S. 213-216 
    Details
    ISSN: 1432-1041
    Keywords: carnitine ; i. v. infusion ; pharmacokinetics ; healthy subjects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics and safety of a brief i. v. infusion of l-carnitine 0, 20, 40 and 60 mg/kg have been investigated in 10 healthy subjects. The diurnal intraindividual variability of plasma carnitine was small (C. V.=3.0, 3.9 and 3.9%, respectively), and the total 24 h excretion in urine was also small and relatively constant: 4.6, 21.5 and 13.0 mg/day in the controls vs 4.6, 20.2 and 6.0 mg/day during treatment in the three subjects to whom saline alone was administered according to a single-blind design. Therefore, the pre-dose level of carnitine was subtracted from the level after dosing for the pharmacokinetic analysis. Plasma carnitine fitted well to a three-compartment open model, with Vc of 0.11–0.20 l/kg and a t1/2γ of 10–23 h. The urine recovery in 24 h was 77.2–95.4%. There were no objective or subjective side-effects attributable to carnitine, so its i. v. infusion is considered to be safe.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00614562
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  • 193
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    Single and multiple dose pharmacokinetics of tenoxicam in the elderly (1988)
    Springer
    European journal of clinical pharmacology 35 (1988), S. 563-566 
    Details
    ISSN: 1432-1041
    Keywords: tenoxicam ; pharmacokinetics ; elderly ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Fourteen elderly subjects (10 women, 4 men) with a mean age of 81 (SD 6.7) years and in need of anti-inflammatory drug treatment were given a single dose of 20 mg tenoxicam. After a drug-free interval of 5 weeks, multiple dose treatment with 20 mg tenoxicam once daily for 56 days was initiated. The single and multiple dose kinetics of tenoxicam were investigated after HPLC determination of tenoxicam in the plasma. The elimination half-life of tenoxicam ranged from 44 to 132 h (mean 71.9 h) with no significant difference between the single and multiple dosage regimens. Tenoxicam reached maximum plasma concentrations after 1.4 and 1.1 h, with values of 3.6 and 15.5 µg·ml−1, for the single and multiple dosage regimen respectively. The corresponding trough values (24-h values) were 1.8 and 11.7 µg·ml−1. A mean accumulation ratio of 5.1 was calculated. The mean increase in the area under the plasma concentration time curves at steady-state was 21% more than predicted from the initial single dose. This deviation from linearity was considered to be of minor clinical significance. The kinetics of tenoxicam in elderly were similar to that published for young healthy volunteers.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00558254
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  • 194
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    Electronic Resource
    Pharmacokinetics of intravenous and oral bolus doses of L-carnitine in healthy subjects (1988)
    Springer
    European journal of clinical pharmacology 35 (1988), S. 555-562 
    Details
    ISSN: 1432-1041
    Keywords: L-carnitine ; pharmacokinetics ; intravenous — oral doses ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of single intravenous and oral doses of L-carnitine 2 g and 6 g has been investigated in 6 healthy subjects on a low carnitine diet. Carnitine was more rapidly eliminated from plasma after the higher dose. Comparing the 2-g and 6-g doses, the t1/2β of the elimination phase (β) was 6.5 h vs 3.9 h, the elimination constant was 0.40 vs 0.50 h−1 and the plasma carnitine clearance was 5.4 vs 6.11 × h−1 (p〈0.025), thus showing dose-related elimination. Saturable kinetics was not found in the range of doses given. The apparent volumes of distribution after the two doses were not significantly different and they were of the same order as the total body water. Urinary recoveries after the 2-g and 6-g doses were 70% and 82% during the first 24 h, respectively. Following the two oral dosing, there was no significant difference in AUCs of plasma carnitine. Urinary recoveries were 8% and 4% for the 2-g and 6-g doses during the first 24 h. The oral bioavailability of the 2-g dose was 16% and of the 6 h dose 5%. The results suggest that the mucosal absorption of carnitine is already saturated at the 2-g dose.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00558253
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  • 195
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    Electronic Resource
    Cadralazine pharmacokinetics — A pilot study (1988)
    Springer
    European journal of clinical pharmacology 35 (1988), S. 571-572 
    Details
    ISSN: 1432-1041
    Keywords: cadralazine ; pharmacokinetics ; hypertension
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00558256
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  • 196
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    The relationship between pharmacokinetics and pharmacodynamics of enoximone in healthy man (1988)
    Springer
    European journal of clinical pharmacology 35 (1988), S. 631-635 
    Details
    ISSN: 1432-1041
    Keywords: enoximone ; heart failure ; inotropic activity ; pharmacokinetics ; pharmacodynamics ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The relationship between the pharmacokinetics and pharmacodynamics of enoximone, a new positive inotropic agent, was investigated in 6 healthy men. The volunteers received single oral and i.v. doses of 3 and 1 mg/kg, respectively, and placebo in a double-blind cross-over trial. Plasma concentrations of enoximone and its sulphoxide metabolite, effects on the corrected electromechanical systole (QS2c), the impedance cardiogram (dZ/dt)/RZ index, blood pressure and heart rate were determined over an 8-h period. Peak effects on QS2c and the (dZ/dt)/RZ index were obtained after approximately 1 h. During the first hour, the cardiac effects lagged behind the high plasma concentrations. Thereafter, the effects on QS2c were closely correlated with the plasma concentrations both of enoximone and its sulphoxide derivative (r≥0.90). The concentration-effect curves of both substances were parallel and were independent of the route of administration. The inotropic activity was not related to the drug level in hypothetical peripheral compartments. The results suggest that determination of plasma enoximone 1 h after administration and thereafter may be useful in assessing the haemodynamic activity of the drug. Should this observation also be present in a clinical situation, plasma enoximone measurements might be a valuable tool in management of patients suffering from heart failure.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00637599
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  • 197
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    Electronic Resource
    Pharmacokinetics of biliary excretion in man. VI. Indocyanine green (1988)
    Springer
    European journal of clinical pharmacology 35 (1988), S. 295-303 
    Details
    ISSN: 1432-1041
    Keywords: indocyanine green ; pharmacokinetics ; biliary excretion ; liver function test
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of Indocyanine Green (ICG) has been studied in 15 patients given 0.5, 1.0 and 2.0 mg · kg−1. The plasma disappearance and biliary excretion rate were measured in patients with tightly fitting catheters under slight negative pressure in order to achieve complete collection of bile. Recovery of unchanged ICG in bile over 18 h after the i.v. injection was 80% of the dose in all three dose groups. Plasma disappearance in all 3 groups was biphasic, showing an initial phase with a t1/2 of 3–4 min and a secondary phase with a dose-dependent apparent t1/2 of 67.6, 72.5 and 88.7 min, respectively. After 0.5 and 1.0 mg · kg−1 the biliary excretion rate curves showed an ascending phase with a mean t1/2 of 5 min and a descending phase with a mean t1/2 of 72 min. It was inferred that the secondary component of the plasma-decay mainly reflected the biliary excretion rate. After 2.0 mg · kg−1 in some patients the biliary excretion curve showed features of saturation; the t1/2 of the descending phase ranged from 73 to 440 min, and the time of maximal excretion was increased from 1.3 to 2.7 h after injection, whilst the mean maximal excretion rate was in the same range as the excretion rate after the 1.0 mg · kg−1 dose. The non-linear pharmacokinetics was only moderately reflected in the measured plasma disappearance patterns. Two compartment analysis of the plasma levels indicated a clearance of 230–260 ml · min−1, whereas the clearance conventionally calculated from the initial t1/2 was 475 ml · min−1. The volume of the central compartment in 70 kg patients was 2.31, which is about the plasma volume. The fictive volume of distribution in the liver (V2) was 70–90 l, indicating marked hepatic storage of ICG. This was probably due to the very low liver-to-plasma transport rate (k21) of 0.006–0.10 min−1. Thus, the biliary excretion of ICG can be quantified by 2-compartment pharmacokinetic analysis of plasma disappearance curves, including a secondary phase. The latter, slow component was apparent at very low plasma levels due to the marked hepatic storage, and it was also influenced by retention of small amounts of impurities or degradation products. Improved detectability of this phase cannot simply be obtained by increasing the dose, since at doses exceeding 1.0 mg · kg−1 non-linear elimination may complicate the pharmacokinetic analysis.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00558268
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  • 198
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    Extent and pharmacokinetic mechanisms of oral atenolol-verapamil interaction in man (1988)
    Springer
    European journal of clinical pharmacology 35 (1988), S. 363-366 
    Details
    ISSN: 1432-1041
    Keywords: verapamil ; atenolol ; drug interaction ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Chronic coadministration of oral verapamil with oral atenolol resulted in a variable increase in atenolol steady-state plasma concentrations in a group of 10 patients on chronic maintenance therapy. Individual subjects showed changes in area under the plasma atenolol concentration-time curve (AUC) of more than 100%, however group comparisons did not achieve statistical significance unless normalized for verapamil dose. Renal clearance of atenolol was shown to be decreased by more than 25% in 2 subjects studied using intravenous dosing of atenolol. This interaction is likely to contribute to the documented clinical intolerance of combinations of atenolol and verapamil.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00561365
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  • 199
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    Pharmacokinetics of intravenous captopril in healthy men (1988)
    Springer
    European journal of clinical pharmacology 35 (1988), S. 367-370 
    Details
    ISSN: 1432-1041
    Keywords: captopril ; pharmacokinetics ; healthy volunteers ; i.v. application
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetic characteristics of intravenously-administered captopril were investigated in 7 healthy men 20 to 33 years old. Capropril, labeled with14C, was given by injection over a 1 min period at mean doses of 2.78 mg (13.8 µCi), 5.67 mg (28.2 µCi) and 11.4 mg (56.8 µCi). Concentrations of unchanged captopril, captopril disulfide, and other metabolites (collectively) were determined in body fluids. Pharmacokinetic parameters were calculated for unchanged captopril, and it was shown that the disposition of intravenously-administered drug was linear with respect to dose over the dosage range studied.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00561366
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  • 200
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    Electronic Resource
    Pharmacokinetics of pirprofen and its pyrrol metabolite in elderly patients (1988)
    Springer
    European journal of clinical pharmacology 35 (1988), S. 379-383 
    Details
    ISSN: 1432-1041
    Keywords: pirprofen ; pharmacokinetics ; old age
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Plasma concentrations of pirprofen and of its pyrrol metabolite were assessed in 9 elderly patients (3 males, 6 females; mean age 76 years) suffering from chronic degenerative disease. Pirprofen 400 mg in 4 ml was administered i.m. and the pharmacokinetic profile of the drug and the metabolite was calculated. The AUC, Cmax and t1/2 of pirprofen were similar to those found in previous studies, and, as expected, those parameters for the pyrrol metabolite were lower (Cmax=2.8 µg/ml−1; tmax=6.4 h; AUC(0–32)=56.5 µg · h · ml−1). One patient (n=8) showed different pharmacokinetic behaviour, which is discussed. The data suggest that age has little influence on the pharmacokinetic of pirprofen, although unpredictable responses should always be considered in clinical practice.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00561368
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