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  • 1985-1989  (256)
  • 1860-1869
  • 1989  (113)
  • 1986  (143)
  • pharmacokinetics  (256)
  • 201
    Electronic Resource
    Electronic Resource
    Renal clearance of sulphinpyrazone in man (1986)
    Springer
    European journal of clinical pharmacology 31 (1986), S. 473-478 
    Details
    ISSN: 1432-1041
    Keywords: sulphinpyrazone ; renal clearance ; pharmacokinetics ; metabolites
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Six healthy young volunteers received a single dose of sulphinpyrazone 200 mg p.o. Plasma concentration and urinary excretion rate curves showed large intersubject variation for sulphinpyrazone and its metabolites. The sulphide metabolite could only be detected in plasma and not before 3–7 h after ingestion. The total recovery in urine of all compounds varied from 30–56% of the dose. In two subjects the mean residence time of sulphinpyrazone was twice as long as in the other subjects (10.4 h compared with 4.6 h), but the area under the plasma concentration-time curve was comparable to that in the others (mean: 3.0 mg·ml−1·min), indicating that drug absorption was quantitatively similar but delayed. The renal clearance of sulphinpyrazone varied from 14–40 ml·min−1 (mean: 28 ml·min−1). In view of the very high plasma protein binding of sulphinpyrazone, active tubular secretion is the predominant mechanism in its renal clearance. The same holds for the sulphone metabolite, which has a mean renal clearance of 24 ml·min−1, and even more for the p-hydroxysulphinpyrazone metabolite, which has a renal clearance of 118 ml·min−1. No unambiguous evidence was found in favour of concentration-dependent renal clearance of sulphinpyrazone or its metabolites over the concentration range studied. The renal clearance, especially of sulphinpyrazone, appeared to be dependent on urine pH and not on urine flow rate.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00613527
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  • 202
    Electronic Resource
    Electronic Resource
    A comparison of the pharmacokinetics and diuretic effects of two loop diuretics, torasemide and furosemide, in normal volunteers (1986)
    Springer
    European journal of clinical pharmacology 31 (1986), S. 21-27 
    Details
    ISSN: 1432-1041
    Keywords: torasemide ; furosemide ; diuretic effects ; pharmacokinetics ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The diuretic effects of torasemide and furosemide at three different steady-state plasma and urinary drug levels were compared in a randomized cross-over study in 6 healthy volunteers. Each trial with either torasemide or furosemide consisted of four consecutive periods of 90 min, the first being a control period, and during the three other periods, increasing doses of drug were administered. Each 90-min period was itself divided into three 30 min blood sampling and urinary collection periods. The urinary losses of water and electrolytes were compensated within each 30-min period by intravenous infusion of saline (NaCl) and 5% glucose solutions, to which KCl was added. A constant dose of calcium gluconate was given to compensate, at least in part, any calcium loss. Data from each 30 min control and the 3 drug dose periods, corresponding to full steady-state conditions, were used for clearance determinations and measurement of plasma and urinary drug concentrations. Urine volume, osmolar clearance, absolute and fractional urinary excretion of sodium, potassium, chloride, calcium and magnesium and creatinine clearance increased similarly after torasemide and furosemide according to the logarithm of the dose of the drug. Free water clearance stabilized at a constant level with torasemide and increased continuously after each dose of furosemide. During each of the three drug administration periods, the plasma levels of torasemide were not significantly different from those of furosemide, whereas the urinary concentrations and absolute excretion rates of torasemide were more than 5-times lower than those of furosemide. The urinary concentrations and excretion rates of both drugs were significantly correlated with their effect on urinary volume (p〈0.05). It is concluded that torasemide is a potent loop diuretic. It acts at lower urinary levels than furosemide. This might indicate more effective binding of torasemide to luminal tubular receptors or an additional effect of this drug on non-luminal receptors.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00541463
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  • 203
    Electronic Resource
    Electronic Resource
    The influence of haemodialysis and haemofiltration on the clearance of Torasemide in renal failure (1986)
    Springer
    European journal of clinical pharmacology 31 (1986), S. 53-55 
    Details
    ISSN: 1432-1041
    Keywords: torasemide ; renal failure ; haemodynamics ; clearance ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The concentration of Torasemide in plasma, dialysate and ultrafiltrate were determined during one haemofiltration and three dialyses. Results show that Torasemide is not significantly eliminated from the blood by these technics.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00541468
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  • 204
    Electronic Resource
    Electronic Resource
    Pharmacokinetic and pharmacodynamic studies following the intravenous and oral administration of the antiparkinsonian drug biperiden to normal subjects (1986)
    Springer
    European journal of clinical pharmacology 29 (1986), S. 735-737 
    Details
    ISSN: 1432-1041
    Keywords: biperiden ; pharmacokinetics ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics and pharmacodynamics (changes in pupil size and salivary flow) of biperiden following a single oral and intravenous dose were investigated in six normal subjects. After the injection plasma concentrations declined biphasically, with half-times of 1.5 h for the rapid phase and 24 h for the terminal phase. Clearance and apparent volume of distribution were high (12 ml·min−1·kg−1 and 24 l·kg−1 respectively). Absorption was rapid but the systemic availability was incomplete (33%), probably due to first-pass metabolism. Central nervous system (CNS) adverse effects and changes in pupil size were observed after both routes of administration while salivary flow was affected only by the injection.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00615970
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  • 205
    Electronic Resource
    Electronic Resource
    Enprofylline: Pharmacokinetics and comparison with theophylline of acute effects on bronchial reactivity in normal subjects (1986)
    Springer
    European journal of clinical pharmacology 30 (1986), S. 21-25 
    Details
    ISSN: 1432-1041
    Keywords: enprofylline ; theophylline ; bronchial reactivity ; histamine inhalation test ; healthy volunteers ; pharmacokinetics ; bronchodilatation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In a double blind, placebo controlled, crossover study the pharmacokinetics and acute effects of enprofylline and theophylline on airway reactivity during histamine challenge were investigated in 10 healthy volunteers. The pharmacokinetic parameters of enprofylline were (mean): elimination half-life 1.9 h, total body clearance 191.1 ml · kg−1 · h−1, volume of distribution 0.48 l · kg−1, and protein binding 49%. Bronchial reactivity in the histamine inhalation test was expressed as the concentration causing a 20% fall in FEV1.0 (PC20). Mean PC20 values were lowest after placebo and highest after theophylline with the enprofylline values in between. Only the difference in PC20 Safter placebo and theophylline was statistically significant (p〈0.05). At the time of determination of the PC20, the serum concentration of enprofylline was between 16.5 and 11.8 µmol/l, and that of theophylline was between 78.3 and 61.1 µmol/l. Adverse actions of enprofylline were nausea (3/10) and cardiovascular reactions (2/10), whereas theophylline mainly caused restlessness (3/10) and tremor (2/10). Thus enprofylline, in one-fifth of the serum concentration of theophylline cannot be regarded as equipotent in terms of bronchoprotection.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00614190
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  • 206
    Electronic Resource
    Electronic Resource
    Antiarrhythmic efficacy of propafenone: Evaluation of effective plasma levels following single and multiple doses (1986)
    Springer
    European journal of clinical pharmacology 30 (1986), S. 665-671 
    Details
    ISSN: 1432-1041
    Keywords: propafenone ; antiarrhythmic drug ; therapeutic range ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In 11 patients with stable premature ventricular beats, the kinetics of single (150 and 300 mg) and multiple (150 mg t.i.d. and 300 mg t.i.d.) oral doses of propafenone were studied with reference to arrhythmia suppression. During the acute phase detectable plasma levels of the drug were achieved only with the higher dose. In 8 out of 10 patients the antiarrhythmic effect was obtained with the 300 mg dose, which was found to predict responsiveness at steady-state. During the chronic phase, antiarrhythmic efficacy was obtained with the lower dose regimen (150 mg t.i.d.) in half of those patients. A wide range of effective plasma levels was observed. The previously suggested therapeutic range (0.5–2.0 µg/ml) was not adequate in predicting either antiarrhythmic activity or adverse effects. The results show the role of propafenone metabolites in determining total antiarrhythmic action.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00608213
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  • 207
    Electronic Resource
    Electronic Resource
    Plasma concentrations of codeine and its metabolite, morphine, after single and repeated oral administration (1986)
    Springer
    European journal of clinical pharmacology 30 (1986), S. 673-677 
    Details
    ISSN: 1432-1041
    Keywords: codeine ; morphine ; pharmacokinetics ; steady-state ; oral administration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Plasma concentrations of codeine and its demethylated metabolite, morphine, were determined after single and repeated oral administration of codeine. Twelve healthy volunteers received two doses of codeine 60 mg, 2.8 h apart. In order to achieve steady-state conditions codeine 60 mg was then taken every 8 h for a further five doses. The plasma concentrations of codeine and morphine after the first, second and seventh doses were analyzed by GC-MS. The maximum plasma concentrations of codeine and morphine were reached about 1 h after administration and this time interval did not change on repeated administration. The peak plasma codeine was higher after the second dose of codeine than after the first and the concentration resembled that at steady-state. For morphine, the plasma concentration did not increase significantly after the second dose. Both after a single dose and during steady-state the plasma concentration of morphine was only 2–3% of that of codeine. It seems unlikely that morphine plays a significant role in the analgesic efficacy of single or repeated doses of codeine.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00608214
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  • 208
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of albendazole in man (1986)
    Springer
    European journal of clinical pharmacology 30 (1986), S. 705-708 
    Details
    ISSN: 1432-1041
    Keywords: albendazole ; hydatid disease ; pharmacokinetics ; man
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of albendazole were investigated in healthy volunteers and in patients receiving albendazole for treatment of hydatid disease. Unchanged albendazole was below detectable limits in plasma, urine, bile and cyst fluid. The major metabolite present in all fluids was the sulfoxide. Maximum concentrations of albendazole sulfoxide in plasma were very variable, probably due to variable absorption of albendazole.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00608219
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  • 209
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of TZU-0460, a new H2-receptor antagonist, in patients with impaired renal function (1986)
    Springer
    European journal of clinical pharmacology 30 (1986), S. 709-712 
    Details
    ISSN: 1432-1041
    Keywords: TZU-0460 ; renal failure ; H2-receptor antagonist ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have studied pharmacokinetics of a new H2-receptor antagonist, TZU-0460, in patients with varying degrees of renal impairment. The apparent volume of distribution at steady-state was 1.70 l/kg, and the plasma protein binding of TZU-0460 or its active metabolite, desacetyl TZU-0460 was less than 10% in normal subjects. These variables were not altered with renal impairment. Sixty percent of TZU-0460 given orally was excreted via the kidney, mainly by tubular secretion. The half-time of elimination was 3.94 h in normal subjects, and was prolonged to 12.13 h in severe renal failure (creatinine clearance below 30 ml/min/1.48 m2). Dosage adjustment of TZU-0460 is necessary in renal failure.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00608220
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  • 210
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of slow-release diltiazem and its effect on atrioventricular conduction in healthy volunteers (1986)
    Springer
    European journal of clinical pharmacology 31 (1986), S. 423-426 
    Details
    ISSN: 1432-1041
    Keywords: Diltiazem ; slow-release tablet ; pharmacokinetics ; atrioventricular conduction ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics and effect of a slow-release and a conventional diltiazem tablet on atrioventricular conduction were compared in a randomized cross-over study after a single dose and at steady state in 12 healthy volunteers. The time to peak concentration was significantly delayed after the slow-release as compared to the conventional tablet, both after a single dose (2.7 vs. 0.9 h) and at steady-state (1.9 vs. 0.9 h). The peak concentration was also significantly reduced. There was no marked loss in bioavailability with the slow-release formulation. The maximal fluctuations in serum diltiazem at steady-state for the slow-release tablet were markedly less than after the conventional tablet (62 vs 87%). The PQ-interval was longer after the conventional tablet as compared to the slow-release tablet (both in doses of 120 mg) after a single dose (187 vs 163 ms) and at steady-state (197 vs 174 ms). The maximal prolongation was seen 1 h after intake of the drug. Heart rate was decreased only by 6–9 beats/min, irrespective of the dose. Slow-release diltiazem appears to have many advantages over a conventional tablet.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00613518
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  • 211
    Electronic Resource
    Electronic Resource
    Pharmacokinetic, haemodynamic and radionuclide studies with nicardipine in coronary artery disease (1986)
    Springer
    European journal of clinical pharmacology 29 (1986), S. 651-657 
    Details
    ISSN: 1432-1041
    Keywords: nicardipine ; angina pectoris ; haemodynamic ; pharmacokinetics ; radionuclide studies
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Pharmacokinetic, haemodynamic and radionuclide studies explored the acute pharmacokinetic and pharmacodynamic actions of nicardipine in patients with coronary heart disease. Nicardipine infusion resulted in dose-related reductions in systolic and diastolic blood pressure and an increased heart rate. Pharmacodynamic activity was evident between 12 and 24 min following 5 and 10 mg i.v. nicardipine but by 3–6 min following the higher doses of 15 and 20 mg; hypotensive activity persisted for up to 2 h. Post-infusion nicardipine concentrations declined biexponentially; however the limited data precluded formal compartmental analysis. Plasma clearance ranged from 5–12 ml/min/kg, and appeared lower than previously reported volunteer data. The haemodynamic actions of nicardipine (10 mg infusion over 10 min) in 6 patients undergoing diagnostic catheterization were reductions in systolic, diastolic and mean systemic arterial pressure and systemic vascular resistance index. Heart rate and stroke volume index increased, and there was a small but statistically significant increase in pulmonary artery occluded pressure. Radionuclide parameters were measured in 20 patients with stable angina, at rest and during supine bicycle exercise, before and 3–5 min after nicardipine 10 mg intravenously. The left ventricular ejection fraction increased by 4% at rest but not during exercise. The left ventricular rest and exercise ejection and filling rates both increased with a concurrently reduced left ventricular ejection time. There was a highly significant inverse relationship between baseline exercise ejection fraction and the response to nicardipine; ejection fraction increased with low initial values but was either unchanged or fell with higher initial values. These data suggest that the acute effects of nicardipine in stable coronary artery disease probably reflect a reduction in left ventricular afterload and an associated augmentation of cardiac pumping performance. The acute circulatory profile of nicardipine appears sufficiently promising to warrant longer-term studies in ischaemic heart disease.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00615954
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  • 212
    Electronic Resource
    Electronic Resource
    The pharmacokinetics of tetrabenazine and its hydroxy metabolite in patients treated for involuntary movement disorders (1986)
    Springer
    European journal of clinical pharmacology 29 (1986), S. 703-708 
    Details
    ISSN: 1432-1041
    Keywords: tetrabenazine ; hydroxytetrabenazine ; pharmacokinetics ; bioavailability ; active metabolite ; movement disorder
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of tetrabenazine and a metabolite, hydroxytetrabenazine, have been investigated in seven patients being treated for involuntary movement disorders. Tetrabenazine had a very low oral systemic availability (mean 0.049±0.032 SD). First-pass metabolism to hydroxytetrabenazine was extensive, and the systemic availability for this metabolite was high (mean 0.81±0.30 SD). Since hydroxytetrabenazine has been reported to be as active as tetrabenazine in depleting brain amines, and is present at much higher plasma concentrations than the parent drug, it is likely that this metabolite is the more important therapeutic moiety.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00615962
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  • 213
    Electronic Resource
    Electronic Resource
    Comparative kinetics of phenobarbital after administration of the acid and the propylhexedrine salt (barbexaclone) (1986)
    Springer
    European journal of clinical pharmacology 29 (1986), S. 729-730 
    Details
    ISSN: 1432-1041
    Keywords: phenobarbital ; propylhexedrine salt ; barbexaclone ; bioavailability ; pharmacokinetics ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The kinetics of phenobarbital (PB) was compared after oral administration of equivalent doses of the drug as the acid or the propylhexedrine salt (barbexaclone) to 7 normal volunteers. The absorption and elimination parameters were very similar. It was concluded that propylhexedrine did not affect the serum kinetics of PB given as barbexaclone.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00615968
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  • 214
    Electronic Resource
    Electronic Resource
    The intra- and inter-subject variability of Nifedipine pharmacokinetics in young volunteers (1986)
    Springer
    European journal of clinical pharmacology 30 (1986), S. 57-60 
    Details
    ISSN: 1432-1041
    Keywords: nifedipine ; pharmacokinetics ; oral contraceptives ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Plasma concentrations of Nifedipine were measured following single oral doses of Nifedipine Slow Release (Adalat Retard) on three separate occasions to young, healthy volunteers of both sexes. Intra- and inter-subject variability were assessed by comparing the pharmacokinetic parameters, AUC, Cmax and T50%AUC. Interindividual variability was less than that observed in other studies with the betablockers, metoprolol and propranolol and there was no evidence of differences between the sexes.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00614196
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  • 215
    Electronic Resource
    Electronic Resource
    Pharmacokinetics and pharmacodynamics of the prostacyclin analogue iloprost in man (1986)
    Springer
    European journal of clinical pharmacology 30 (1986), S. 61-68 
    Details
    ISSN: 1432-1041
    Keywords: iloprost ; prostacyclin analogue ; pharmacokinetics ; platelet aggregation ; healthy male volunteers ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Plasma levels of the prostacyclin analogue, iloprost, were measured by antibody/GC/MS in healthy male volunteers given 1 and 3 ng/kg per min i.v. for 45 min, and 1 µg/kg p.o. Following i.v. infusion, the steady-state plasma levels of iloprost were strictly dose-dependent (46±8 pg/ml and 135±24 pg/ml). The disposition was biphasic with half-lives of 3–4 min and 0.5 h. After oral administration, absorption of the drug was extremely rapid, the maximum plasma level of 251±32 pg/ml being achieved after 10±6 min. The bioavailability was 16±4%. Platelet aggregation induced by 2 µM ADP was reduced by 53% and 68% at the end of the two different infusions, and by 68% 15 min after p.o. administration. The ex-vivo inhibition of platelet aggregation by iloprost was not affected by preceding drug treatment. The cAMP content of platelets was increased by a factor of 2.5 at the end of the infusions and to a lesser extent 15 min after oral dosing. A slight increase in heart rate occurred during the infusion and within 30 min after oral administration; blood pressure was virtually unaffected. Except for transient side-effects (facial flush and headache) no adverse reactions were observed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00614197
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  • 216
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of methysergide and its metabolite methylergometrine in man (1986)
    Springer
    European journal of clinical pharmacology 30 (1986), S. 75-77 
    Details
    ISSN: 1432-1041
    Keywords: methysergide ; methylergometrine ; first-pass metabolism ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Five healthy men were given 1.0 mg methysergide maleate intravenously and 2.7 mg methysergide maleate orally in a cross-over study. The systemic availability of methysergide was only 13%, most probably due to a high degree of first-pass metabolism to methylergometrine. We also found evidence of extrahepatic clearance of methysergide. After oral administration the plasma concentrations of the metabolite were considerably higher than those of the parent drug and the area under the plasma concentration curve (AUC) for methylergometrine was more than ten times greater than for methysergide. Our findings may be relevant to the treatment of migraine if methylergometrine contributes to the effect of methysergide. Methylergometrine had a significantly longer elimination half-life than methysergide (223±43 min vs 62.0±8.3 min and 174±35 min vs 44.8±8.1 min in the oral and intravenous studies respectively).
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00614199
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  • 217
    Electronic Resource
    Electronic Resource
    Effect of cirrhosis and renal failure on the kinetics of clotiazepam (1986)
    Springer
    European journal of clinical pharmacology 30 (1986), S. 89-92 
    Details
    ISSN: 1432-1041
    Keywords: clotiazepam ; liver cirrhosis ; renal insufficiency ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The kinetics of a single 5-mg oral dose of the thienodiazepine clotiazepam was evaluated in a series of patients with biopsy-proven cirrhosis, and in patients with renal insufficiency requiring maintenance hemodialysis, compared to healthy matched controls. Clotiazepam volume of distribution (Vz) was significantly smaller in cirrhotic patients than in controls (1.83 vs 2.57 l/kg), and total clearance was likewise reduced (2.15 vs 3.15 ml/min/kg). Elimination half-life was similar between groups (10.0 vs. 10.2h). There were no significant differences between renal failure and control patients in clotiazepam Vz, oral clearance, or elimination half-life. Thus cirrhosis is associated with reduced clearance of clotiazepam, probably due to impairment of its microsomal oxidation. However clotiazepam disposition is not significantly altered in dialysis-dependent renal insufficiency patients.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00614202
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  • 218
    Electronic Resource
    Electronic Resource
    The effects of age and chronic liver disease on the elimination of temazepam (1986)
    Springer
    European journal of clinical pharmacology 30 (1986), S. 93-97 
    Details
    ISSN: 1432-1041
    Keywords: temazepam ; liver disease ; elimination ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of the newer 1, 4 benzodiazepine temazepam were evaluated in 16 healthy subjects aged 18–92 years and in 15 cirrhotic patients, to ascertain the effect of ageing and liver disease. The data were analysed both by classic two compartment and by non-compartmental methods. The mean elimination half-life in the control subjects was 15.5 h, considerably longer than previous estimates. No correlation was found between age and pharmacokinetic parameters. The cirrhotic group showed no statistically significant difference in the pharmacokinetic parameters nor in the urinary recovery of the dose from the control group. Temazepam plasma protein binding was assessed in a second group of 9 cirrhotics of similar severity to the main group and in matched controls. When these binding data were applied to the mean clearance data, a modest although not statistically significant, reduction in free drug clearance was observed in the cirrhotic group. This study adds further support to the observation that drugs which undergo ether glucuronidation have normal elimination patterns in patients with liver disease. Temazepam may prove to be a useful hypnotic sedative in patients with liver disease.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00614203
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  • 219
    Electronic Resource
    Electronic Resource
    Cirrhosis of the liver markedly impairs the elimination of mexiletine (1986)
    Springer
    European journal of clinical pharmacology 30 (1986), S. 83-88 
    Details
    ISSN: 1432-1041
    Keywords: mexiletine ; cirrhosis of the liver ; antiarrhythmic agents ; pharmacokinetics ; intravenous administration ; protein binding
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary To study the effects of cirrhosis of the liver on the pharmacokinetics of mexiletine a single i.v. dose of 200 mg was administered to six cirrhotic patients and to six healthy controls. The distribution of mexiletine in both study groups was similar, as indicated by similar values of V1 and Vss, but it tended to occur more slowly in the cirrhotics. The plasma protein binding of mexiletine was unchanged in the patients with cirrhosis. The elimination of mexiletine was markedly retarded in the cirrhotics, as indicated by its lower total clearance (2.31 vs. 8.27 ml/kg/h,) lower total elimination rate constant (0.059 vs 0.353 h−1), and longer elimination half-life (28.7 vs 9.9 h). The antipyrine half-life was 38.3 h in the patients and 14.7 h in the controls. One healthy volunteer had a Morgagni-Stokes-Adams type of syncopal attack 5 min after administration of mexiletine due to disturbance of AV conduction induced by the drug. Thus, on a pharmacokinetic basis the loading dose of mexiletine need not be modified in cirrhotic patients, whereas the maintenance dosage should be reduced to one fourth — one third of the usual dose.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00614201
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  • 220
    Electronic Resource
    Electronic Resource
    Ceftriaxone pharmacokinetics following multiple intramuscular dosing (1986)
    Springer
    European journal of clinical pharmacology 30 (1986), S. 109-112 
    Details
    ISSN: 1432-1041
    Keywords: ceftriaxone ; intramuscular ; pharmacokinetics ; steady-state
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The steady-state pharmacokinetics and tolerance of ceftriaxone after multiple i.m. doses of 0.5 and 1 g q12 h for 3.5 days were investigated in 12 healthy, adult volunteers. Ceftriaxone was rapidly absorbed after i.m. administration with mean peak times ranging from 1.3 to 1.9 h. Steady-state plasma concentrations were apparent after the third dose of both dosage regimens, with trough plasma concentrations of 24±6 and 39±8 µg/ml (mean±SD) after the 0.5 and 1 g q12 h regimens, respectively. Multiple i.m. administrations of ceftriaxone did not alter its elimination half-life; however, small increases were observed in the plasma clearance and volume of distribution at the 1-g regimen. These increases were attributed to the non-linear binding of ceftriaxone to human plasma proteins, and are therapeutically unimportant. Ceftriaxone was well tolerated and serious or lasting adverse reactions were not encountered in the study.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00614206
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    Pharmacokinetics of dezocine, a new analgesic: Effect of dose and route of administration (1986)
    Springer
    European journal of clinical pharmacology 30 (1986), S. 121-123 
    Details
    ISSN: 1432-1041
    Keywords: dezocine ; opioid analgesics ; pharmacokinetics ; healthy volunteers ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of intravenous (IV) dezocine, and bioavailability of intramuscular (IM) and subcutaneous (SQ) dezocine, were evaluated in healthy male volunteers. Elimination half-life following 5, 10, and 20 mg IV doses averaged 2.6–2.8 h, and was independent of dose. Clearance decreased slightly, although significantly, with dose. After Deltoid IM injection, dezocine was rapidly absorbed (peak level: 0.6 h after dose), with bioavailability 97%. Thus dezocine has extensive distribution, high clearance and short half-life over a range of IV doses. It is rapidly and completely absorbed following IM or SQ administration.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00614208
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    Comparison of single and multiple dose pharmacokinetics of theophylline using stable isotopes (1986)
    Springer
    European journal of clinical pharmacology 30 (1986), S. 113-120 
    Details
    ISSN: 1432-1041
    Keywords: theophylline ; pharmacokinetics ; stable isotopes ; diurnal variation ; single dose administration ; multiple dose administration ; systemic availability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Theophylline, enriched with the stable isotopes13C and15N, was administered intravenously in a dose of 10 mg to 8 healthy men following single (200 mg) and multiple (200 mg 8-hourly for 5 days) oral dose administration of aminophylline. Total plasma clearance, volume of distribution, and half-time determined from the intravenous data were similar, demonstrating that the pharmacokinetics of theophylline after chronic dosing can be predicted from the pharmacokinetics of a single dose. With chronic oral dosing, however, the mean trough concentration was 12% higher at 9 a.m. than at 5 p.m., the end of the dose interval (3.94±0.55 vs. 3.50±0.45 µg·ml−1). The AUC following oral dosing was 25% higher in the multiple dose study than in the single dose study. Simulation analysis suggested that these results could be explained by diurnal variation in the clearance or absorption rate or a combination of both. Thus, the systemic availability of theophylline measured during a single dosage interval after chronic oral dosing to steady state would be overestimated in comparison with that measured after a single oral dose.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00614207
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    Single dose oxazepam has no effect on acetaminophen clearance or metabolism (1986)
    Springer
    European journal of clinical pharmacology 30 (1986), S. 127-129 
    Details
    ISSN: 1432-1041
    Keywords: oxazepam ; acetaminophen clearance ; metabolite formation ; glucuronidation ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The metabolism of acetaminophen and oxazepam in humans is mainly dependent on the microsomal capacity for glucuronide conjugation. The clearance of acetaminophen and the formation of metabolites were evaluated in 7 patients before and during concomitant administration of oxazepam 30 mg. The subjects received a single 500 mg dose of acetaminophen i.v. and concentrations in plasma were measured for 360 minutes and in urine for 24 h in order to estimate the production of metabolites. The single therapeutic dose of oxazepam had no effect on the clearance of acetaminophen or on formation of its metabolites.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00614210
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  • 224
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    Treatment of essential hypertension with felodipine in combination with a diuretic (1986)
    Springer
    European journal of clinical pharmacology 30 (1986), S. 133-139 
    Details
    ISSN: 1432-1041
    Keywords: felodipine ; hydrochlorothiazide ; essential hypertension ; calcium antagonist ; pharmacokinetics ; plasma noradrenaline ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In a double-blind cross-over study, the effect on blood pressure (BP), heart rate (HR) and plasma noradrenaline concentration (pNA) of placebo or felodipine given in addition to hydrochlorothiazide was studied in 12 male patients with essential hypertension, not satisfactorily controlled with the diuretic alone. The first dose of felodipine decreased BP and increased HR for about 6 h. After 4 weeks of treatment with felodipine, BP was reduced for 24 h, whereas HR was only transiently increased. The elimination half-life of felodipine was about 23 h. The plasma noradrenaline concentration increased after felodipine and serum uric acid decreased. Side-effects were few and usually mild.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00614290
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    Pharmacokinetics and pharmacodynamics in man of the dopamine antagonist ergot derivative, bromerguride (1986)
    Springer
    European journal of clinical pharmacology 31 (1986), S. 165-168 
    Details
    ISSN: 1432-1041
    Keywords: bromerguride ; dopamine antagonist ; pharmacokinetics ; pharmacodynamics ; prolactin level ; side-effects ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The plasma levels and urinary excretion of the dopamine antagonist, bromerguride, were measured by radioimmunoassay in healthy male volunteers given 50 µg i.v. and oral doses of 1 and 2 mg. Plasma prolactin was also measured by radioimmunoassay. Following i.v. injection, the concentration of bromerguride declined biphasically, with half-lives of 7 min and 1.2h. The total clearance was 32 ml·min−1·kg−1 and the apparent volume of distribution was 3.6 l/kg. The bioavailability of oral bromerguride was 29% after 1 mg and 25% after 2 mg. The drug was almost totally metabolized and less than 0.05% of the dose was excreted in urine in 24 h after oral administration. Plasma prolactin levels were increased in a dose-dependent manner for about 8 h. Side-effects were minimal, mainly being tiredness and headache in some of the volunteers.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00606653
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    Pharmacokinetics of tenoxicam in patients with impaired renal function (1986)
    Springer
    European journal of clinical pharmacology 29 (1986), S. 697-701 
    Details
    ISSN: 1432-1041
    Keywords: tenoxicam ; renal insufficiency ; non-steroidal antiinflammatory agents ; protein binding ; metabolism ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of tenoxicam after a single oral dose of 20 mg has been studied in 12 patients with various degrees of decreased renal function. Unchanged tenoxicam and its 5′OH-metabolite in plasma and urine were determined by HPLC. The mean areas under the plasma concentration-time curve (138±53 µg/ml·h) and terminal half-lives in patients with impaired renal function did not differ from values previously reported in normal volunteers, nor did the peak concentration of tenoxicam. The half-life of 5′OH-tenoxicam and unchanged tenoxicam where the same. The urinary excretion of 5′OH-tenoxicam fell with decreasing renal function. Thus no dosage adjustment should be necessary and the usual daily dose of tenoxicam may be administered once daily also to patients with renal failure.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00615961
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    The pharmacokinetics after intravenous and oral administration in man of theα 2-adrenoreceptor antagonist idazoxan (RX781094) (1986)
    Springer
    European journal of clinical pharmacology 29 (1986), S. 743-745 
    Details
    ISSN: 1432-1041
    Keywords: idazoxan ; pharmacokinetics ; alpha 2-adrenoceptor antagonist ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A high performance liquid chromatographic method was developed for the quantitative determination of idazoxan in plasma. The assay was used to study the disposition of the drug after intravenous infusion and oral administration to five normal subjects. After i.v. administration the kinetics could be described by a two compartment model with a mean elimination half life of 4.20 h. The mean calculated volume of distribution during the elimination phase was 3.20 l/kg−1 and the mean plasma clearance was 824 ml min−1. After oral administration a lag period before onset of absorption was observed in all five volunteers, the plasma levels declining monoexponentially from the peak concentration with a mean elimination half life of 5.58 h. The absolute availability varied between 26% and 41% with a mean value of 34%. Invitro measurements produced a blood/plasma ratio of 1.3 for idazoxan.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00615972
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    Pharmacokinetics of temazepam in geriatric patients (1986)
    Springer
    European journal of clinical pharmacology 30 (1986), S. 745-747 
    Details
    ISSN: 1432-1041
    Keywords: temazepam ; pharmacokinetics ; geriatric patients ; benzodiazepines
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A single dose of temazepam 10 mg, as a solution in soft gelatin capsules, was given to 10 fasting geriatric in-patients (mean age 83 years) in a stable clinical condition. The mean peak plasma concentration was 306 ng/ml, with a median time of 0.75 h to peak concentration. Temazepam was eliminated from plasma in a biexponential manner, with a distribution phase (mean t1/2α=0.7 h) predominating for 3 h. The drug had a mean elimination half-life of 8.7 h. In a chronic study, in which temazepam 10 mg p.o. was given nightly to 13 patients, the plasma concentrations on Days 3, 5, 8, 12 and 15 were not significantly different from each other, showing rapid attainment of steady state levels and the lack of drug accumulation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00608229
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    5-Aminosalicylic acid in patients with an ileo-rectal anastomosis (1986)
    Springer
    European journal of clinical pharmacology 31 (1986), S. 23-26 
    Details
    ISSN: 1432-1041
    Keywords: sulphasalazine ; Pentasa ; slow release preparation ; 5-aminosalicylic acid ; ileo-rectal anastomosis ; ulcerative colitis ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of 5-aminosalicylic acid (5-ASA) from sulphasalazine (SASP) and the slow-release 5-ASA preparation Pentasa was investigated in a cross-over study in 9 otherwise healthy patients with an ileo-rectal anastomosis. The 24-hour recoveries of the drugs were 90.5% and 84.7%, respectively. The median release of 5-ASA from SASP was 50% and from Pentasa 75%. Equal amounts of 5-ASA (18.0% vs 17.9%) were found in the faeces, and a significantly larger amount (4.4% vs 28.9%) of the metaboliteN-acetyl-5-aminosalicylic acid (ac-5-ASA) was found in faeces following Pentasa. A larger amount of 5-ASA was absorbed and subsequently excreted in the urine, mainly as the metabolite (2.5% vs 20.5%) from Pentasa. This confirms previous results in ileostomized patients treated with Pentasa. The present findings also demonstrate that bacterial azo-reduction of SASP in patients with ileorectal anastomosis may be an adequate way to deliver 5-ASA in this type of patient. Both treatments may be used in these patients during a flare up of ulcerative colitis, but randomized studies are needed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00870980
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    Pharmacokinetics and metabolism of quinidine in extensive and poor metabolisers of sparteine (1986)
    Springer
    European journal of clinical pharmacology 31 (1986), S. 69-72 
    Details
    ISSN: 1432-1041
    Keywords: quinidine ; sparteine ; pharmacokinetics ; drug oxidation ; polymorphism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics and metabolism of quinidine were investigated in extensive and poor metabolisers of sparteine. No differences in plasma clearance, terminal half life, volume of distribution or cumulative urinary excretion of quinidine, 3-hydroxyquinidine and quinidine-N-oxide were observed between phenotypes. Thus, it is unlikely that quinidine metabolism is controlled by the sparteine/debrisoquine gene locus.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00870989
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    Pharmacokinetics of intravenous and intraperitoneal ceftriaxone in chronic ambulatory peritoneal dialysis (1986)
    Springer
    European journal of clinical pharmacology 31 (1986), S. 479-483 
    Details
    ISSN: 1432-1041
    Keywords: ceftriaxone ; dialysis ; continous ambulatory peritoneal dialysis ; pharmacokinetics ; intraperitoneal administration ; intravenous administration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The kinetics of ceftriaxone was investigated in 8 patients without infection, who were receiving continuous ambulatory peritoneal dialysis (CAPD). Ceftriaxone 1 g was injected i.v. and 1 g was given intraperitoneally in the CAPD fluid during a 4-h dwell time. Ceftriaxone was assayed by HPLC. After intravenous administration, the kinetic parameters of ceftriaxone were: plasma t1/2, 12.3 h, total plasma clearance, 14.0 ml/min, volume of distribution at steady state 0.18 l/kg, and peritoneal clearance 0.59 ml/min. Over 72 hours only 5.5% of the dose was eliminated by the peritoneal route. After intraperitoneal administration, ceftriaxone rapidly appeared in serum; the absorption t1/2 was 1.1 h and the mean peak concentration was 38.8 µg/ml. The absorption of ceftriaxone from the peritoneal space was 39%. A single 1.0 g IP dose led to serum and dialysate concentrations of ceftriaxone above the minimum inhibitory concentration for susceptible pathogens for 24 hours.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00613528
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    Diuretic activity, safety and pharmacokinetics of torasemide during chronic treatment in normal subjects (1986)
    Springer
    European journal of clinical pharmacology 31 (1986), S. 1-7 
    Details
    ISSN: 1432-1041
    Keywords: torasemide ; diuretic activity ; pharmacokinetics ; healthy subjects ; side-effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Torasemide 40 mg/day p.o. was administered for 21 days to 8 healthy volunteers to investigate its pharmacodynamics, pharmacokinetics and safety on chronic administration. It induced a highly significant initial increase in 24-h urinary volume and 24-h excretion of sodium and chloride, but its affect diminished after the first days. On Days 0, 1, 10 and 21 the experiement was divided in 3 clearance phases, extending from 0 to 2 h, 2 to 6 h and 6 to 24 h after dosing. The fractional excretion of sodium, chloride, potassium, calcium, magnesium and inorganic phosphates peaked during the first 2 h and returned almost to the control value during the following two clearance phases. The phase-dependent changes were significant for all electrolytes, except for potassium and inorganic phosphate. Plasma electrolyte levels remained constant throughout the study, except for a small decrease in chloride and potassium and for an increase in calcium and magnesium. Fasting blood glucose and glucose tolerance test were unaffected. A small but significant decrease in LDL-cholesterol was observed on Day 10. Other plasma lipid components showed minor changes. Plasma uric acid levels were moderately increased. There was no significant change of the creatinine clearance. Body weight fell significantly (by about 2 kg) during the study. Tonal audiometry was normal before and after the study. There was no significant difference between the plasma levels of torasemide on Days 1, 10 and 21, nor between its elimination half-life on Days 1 and 21. Side-effects consisted mainly of fatigue and low-back pain on days of intense diuresis. There were no toxic symptoms. ECG recordings and blood pressure remained within normal limits.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00541460
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    Comparative analysis of the pharmacokinetics of unsubstituted N1-derivatives of 1,4-benzodiazepine (1986)
    Springer
    Bulletin of experimental biology and medicine 101 (1986), S. 206-209 
    Details
    ISSN: 1573-8221
    Keywords: 1,4-benzodiazepines ; pharmacokinetics ; plasma/brain concentration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00836121
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    Pharmacokinetics of a water-soluble antioxidant of 3-hydroxypyridine type (1986)
    Springer
    Bulletin of experimental biology and medicine 101 (1986), S. 333-335 
    Details
    ISSN: 1573-8221
    Keywords: antioxidant ; 3-hydroxypyridines ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00835938
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    Radioimmune and radioreceptor study of the pharmacokinetics of the enkephalin analog dalargin in man (1986)
    Springer
    Bulletin of experimental biology and medicine 101 (1986), S. 783-785 
    Details
    ISSN: 1573-8221
    Keywords: dalargin ; pharmacokinetics ; enkephalins
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00839605
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  • 236
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    A dispersion model of hepatic elimination: 2. Steady-state considerations-influence of hepatic blood flow, binding within blood, and hepatocellular enzyme activity (1986)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 14 (1986), S. 261-288 
    Details
    ISSN: 1573-8744
    Keywords: hepatic elimination ; hepatic clearance ; availability ; intrinsic clearance ; pharmacokinetics ; dispersion model ; well-stirred model ; tube model ; distributed model ; blood flow ; binding within blood ; hepatocellular enzyme activity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The dispersion model of hepatic elimination is based on the distribution of residence times of blood elements within the liver. The model has two asymptotic solutions corresponding to the “wellstirred” model (complete mixing of blood elements) and the “parallel-tube” model (no variation in residence times of blood elements). The steady-state form of the dispersion model relevant to pharmacokinetic analysis is developed and explored with respect to changes in blood flow, in binding within blood, and in hepatocellular enzyme activity. Literature data are used to evaluate discrepancies among the predictions of the dispersion, well-stirred, and tube models. It is concluded that the dispersion model is consistent-with the data. The limitations of steady-state perfusion experiments to estimate the residence time distribution of blood elements within the liver are considered.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01106707
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  • 237
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    In vivo interaction of the enantiomers of disopyramide in human subjects (1986)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 14 (1986), S. 335-356 
    Details
    ISSN: 1573-8744
    Keywords: disopyramide ; pharmacokinetics ; stereoisomers ; antiarrhythmic agents
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Disopyramide, an antiarrhythmic agent, is marketed as a racemic mixture of two enantiomers. The racemic drug has unusual pharmacokinetic properties because of its concentration-dependent binding to plasma proteins in the therapeutic plasma concentration range. This study examined, in healthy subjects, the individual pharmacokinetic properties of both total and unbound d-and ldisopyramide in plasma after intravenous administration of each enantiomer separately (1.5mg/kg).Also investigated is the pharmacokinetics of total d-and l-disopyramide in plasma after intravenous administration of a pseudoracemate. Both d-and l-disopyramide are found to exhibit concentration-dependent binding to plasma proteins, with d-disopyramide being more avidly bound at lower concentrations. The stereoselective, concentration-dependent binding to plasma proteins resulted in distinct pharmacokinetic properties when the enantiomers were given together as the pseudoracemate. d-Disopyramide had a lower plasma clearance and renal clearance, a longer half-life, and a smaller apparent volume of distribution than l-disopyramide. However, when the enantiomers were administered separately, there were no differences in the clearance, renal clearance, and volume of distribution between enantiomers calculated from either total or unbound drug concentrations. The results reveal an important pharmacokinetic interaction between the enantiomers of disopyramide when given as a racemic mixture, which may be dose-dependent and is not apparent upon administration of the enantiomers separately.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01059195
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    The impact of neglecting nonlinear plasma-protein binding on disopyramide bioavailability studies (1986)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 14 (1986), S. 365-379 
    Details
    ISSN: 1573-8744
    Keywords: disopyramide ; bioavailability ; protein binding ; nonlinear ; sustained release ; pharmacokinetics ; ultrafiltration ; immunoassay
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Disopyramide has nonlinear protein binding and thus the relationship between the extent of its bioavailability and AUC,the area under the plasma concentration-time curve, is (1) nonlinear and (2) absorption rate-dependent. The unbound species follows linear pharmacokinetics. A solution of disopyramide, the innovator's product, and two generic formulations were found to be statistically indistinguishable in their bioavailability of disopyramide, whether comparison was based upon AUCor area under the plasma unbound concentration-time curve (AUCu).The AUCand AUCugave similar results because of truly similar bioavailability, coupled with sufficiently similar release rates, among the four preparations chosen for study. The concentration dependence of disopyramide protein binding and the time course of unbound plasma concentrations were fit by models which then allowed prediction of AUCunder various biopharmaceutical scenarios. Nonlinear binding of disopyramide to plasma proteins renders AUCan insensitive parameter for the discrimination of products with different extents of bioavailability; immediate release products allowing bioavailabilities of 75 or 125% relative to the solution can generate AUCs86 and 112%, respectively, of that from the solution. Nonlinear binding, furthermore, leads to a tendency for AUC tooverestimate the bioavailability of slower release products in single-dose studies; if AUCwere the index of bioavailability, products permitting the same bioavailability as the solution but releasing over 12 hr could appear to allow 114% relative bioavailability. Moreover, in some situations the bias arising from the insensitivity of AUCto product differences can be reinforced by the dependence of AUCon release rate; an apparent relative bioavailability of 80% can be achieved by a 12-hr release product allowing a true relative bioavailability of a mere 58%. While multiple-dose studies appear largely to avoid the tendency to overestimate low bioavailability in slow-release products, in these studies AUCappears to be even more insensitive in resolving discrepancies between products. Assay technology now available makes AUCua feasible and more reliable index of bioavailability than AUCwhen plasma protein binding of drugs is nonlinear.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01059197
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    On the pharmacokinetics of 16-acetyl-gitoxin and its bioavailability from pengitoxin-containing tablet formulations (1986)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 14 (1986), S. 357-364 
    Details
    ISSN: 1573-8744
    Keywords: 16-acetyi-gitoxin ; pengitoxin ; pharmacokinetics ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract In six volunteers the pharmacokinetics of 16-acetyI-gitoxin (16AG, 0.5mg) administered intravenously (A1) and as an oral solution (A2) and of pengitoxin (PAG, 0.6 mg) administered intravenously (A3) was evaluated. In six volunteers the bioavailability of 16AG from two PAG tablet formulations (1.2 mg) (B2, B3) was measured by comparison with the absorption after administration of a pengitoxin solution (1.2mg) (B1). In both studies the test was performed using a crossover design. After a single i.v. injection of equimolar doses, 16AG and PAG showed similar mean kinetic parameters: t 1/2 =51.6hr (16AG) and 60.8 hr (PAG), CL=11.7ml min−1 (16AG) and 12.7ml min−1 (PAG), CLR=4.1 ml min−1 (16AG) and 4.2ml min−1 (PAG). The 16AG was absorbed from solution with a mean half-life of 0.2hr to an extent of 98.6%. The mean urinary excretion /Ae(0, 4)/ of 16AG amounted to 24.6% (A1), 20.8% (A2) and 28.1% (A3). On the basis of AUCvalues, the mean bioavailability of PAG from either tablet formulation amounted to 79.6% (B2) and 89.6% (B3). The pharmacokinetic parameters of 16AG (PAG) are closer to those of digitoxin than those of digoxin. In general, 16AG is characterized as a digitoxin with a digoxin-like elimination half-life.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01059196
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    Pharmacokinetics of isosorbide dinitrate and its mononitrate metabolites after intravenous infusion (1986)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 14 (1986), S. 1-17 
    Details
    ISSN: 1573-8744
    Keywords: isosorbide dinitratekw]isosorbide 2-mononitrate ; isosorbide 5-mononitrate ; metabolism ; pharmacokinetics ; modeling ; simultaneous estimation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Plasma concentrations of isosorbide dinitrate (ISDN) and its two active metabolites 2-isosorbide mononitrate (2-ISMN) and 5-isosorbide mononitrate (5-ISMN) have been measured during and for 6 hr after intravenous infusion at a rate of 2.5mg/hr during 1.75 hr in six cardiac patients, by a capillary gas chromatographic method. Data were analyzed by simultaneous modeling of the observed kinetics of the three compounds. Two or three phases were detected on the postinfusion ISDN concentration-time curves. ISDN concentrations declined with a mean terminal half-life of 2.81 hr±0.7 SD. The mean systemic clearance of ISDN (2.9 L/min ±0.7 SD) and its mean total volume of distribution (259 L +- 48 SD) were relatively high. Plasma 5-ISMN concentrations were 5- to 6-fold greater than those of 2-ISMN during the whole observation period. Maximum levels of 2-ISMN (6.7 ng/ml ± 0.9 SD) and of 5-ISMN (27 ng/ml ± 6 SD) occurred within a few minutes after the end of infusion. The mean half-lives of 2-ISMN (1.59 hr± 0.19 SD) and of 5-ISMN (3.78 hr± 0.79 SD) estimated by the model were smaller than those calculated by a model-independent method (2.95 hr± 0.41 SD and 5.98 hr± 2.22, respectively), but were in good agreement with those reported in the literature following separate administration of both metabolites to man. This study shows how such modeling can distinguish between metabolite formation and elimination processes and allow the determination of metabolite half-lives after administration of the precursor drug.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01059280
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    Physiological pharmacokinetic modeling ofcis-dichlorodiammineplatinum(II) (DDP) in several species (1986)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 14 (1986), S. 131-155 
    Details
    ISSN: 1573-8744
    Keywords: pharmacokinetics ; physiological model ; cisplatin ; DDP ; cis-dichlorodiammineplatinum(II)
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract A physiological pharmacokinetic analysis ofcis-dichlorodiammineplatinum(II) (DDP) is presented for the rabbit, dog, and human. The results are compared to a previous analysis for the rat. DDP binds irreversibly to low-molecular weight nucleophiles and macromolecules to form mobile and fixed metabolites at rates which are tissue-specific. The rate constant for the formation of fixed metabolite in plasma, determined by in vitro incubation, ranges from 0.004 to 0.008 min−1.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01065258
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    Receptor-mediated model relating anticonvulsant effect to brain levels of camazepam in the presence of its active metabolites (1986)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 14 (1986), S. 309-321 
    Details
    ISSN: 1573-8744
    Keywords: camazepam ; temazepam ; oxazepam ; pharmacokinetics ; anticonvulsant effect ; radioreceptor assay ; rat ; mouse
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract In a displacement test using3H-diazepam as a radioligand, the in vitro affinities of metabolites of camazepam (CZ) for the benzodiazepine receptors were 1–50 times more potent than that of CZ. In contrast, only three metabolites (temazepam, oxazepam, and hydroxy CZ), as well as CZ itself, exhibited an in vivo affinity parallel to their ability to protect against pentylenetetrazole-induced clonic convulsion in rats. In addition, CZ and these active metabolites displaced the radioligand from their receptor sites in a concentration-dependent saturable manner, indicating the competitive bimolecular interaction of these molecules with their receptors. The percent anticonvulsant effect was a nonlinear, single-valued function of the in vivo percent displacement of specific3H-diazepam binding, independent of these displacers after i.v. dosing; this relationship could be approximated by the Hill equation. On the basis of these findings, a receptor-mediated model, including the Langmuir equation to describe the receptor binding-brain concentration relationship and the Hill equation to accommodate the anticonvulsant effect-receptor binding relationship, was constructed. This model was found to adequately relate the time course values of anticonvulsant effect and of brain levels of CZ and its active metabolites after oral administration. These results demonstrate that CZ and its active metabolites exert anticonvulsant effect by competitive binding to the benzodiazepine receptors.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01106709
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    Effect of caffeine on ceftriaxone disposition and plasma protein binding in the rat (1986)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 14 (1986), S. 397-408 
    Details
    ISSN: 1573-8744
    Keywords: caffeine ; ceftriaxone ; plasma ; tissue ; pharmacokinetics ; compartment model ; protein binding
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Previous studies have shown that caffeine can affect drug kinetics by altering drug binding to plasma protein, drug absorption, or drug distribution. In this study, the effect of caffeine on the in vivoprotein binding and the disposition of ceftriaxone (a highly protein-bound cephalosporin) were investigated in the rat. Ceftriaxone 100mg/kg and caffeine 20mg/kg were i.v. injected via the tail vein and ceftriaxone in plasma, plasma filtrate, urine, feces, and tissues (brain, heart, kidney, liver, gut, lung, and muscle) was assayed by HPLC with UV detection. The fraction of free ceftriaxone in plasma ranged from 5.6 to 32.8% of total ceftriaxone (3–347 μg/ml) without caffeine and showed no alteration by caffeine. The total amount of ceftriaxone excreted in urine and feces was increased significantly (p〈0.05)from 13.1±1.8mg (mean±SD, 54.6% of total) to 15.3 ±1.1 mg (63.8% of total) by caffeine coadministration. The terminal half-life of ceftriaxone in plasma was shortened from 59 to 47 min, and the area under the plasma drug concentration-time curve (AUC)was reduced from 612 to 516 μg hr/ml Although the peak drug concentrations and the times of peak concentration of ceftriaxone in tissues were not altered by caffeine administration, the elimination of ceftriaxone was increased, as indicated by generally shorter half-lives (decreases ranged from 17.5% in liver to 34.2% in brain) and lower AUCvalues (from 9.0% in heart to 54.5% in brain). These results suggest that caffeine does not alter the protein binding of ceftriaxone, but enhances the elimination of ceftriaxone in the rat.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01059199
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    Drug pharmacokinetics and the carbon dioxide breath test (1986)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 14 (1986), S. 29-49 
    Details
    ISSN: 1573-8744
    Keywords: carbon dioxide ; breath test ; pharmacokinetics ; metabolite ; extraction ratio ; aminopyrine ; caffeine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The interrelationship of the pharmacokinetics of a drug and the expiration of carbon dioxide formed as a metabolite have been studied. The pharmacokinetic characteristics of the drug that affect the usefulness of the carbon dioxide excretion as a measure of liver function were examined by means of computer simulations. The parent drug extraction ratio, fraction demethylated, volume of distribution, and absorption rate of an oral dosage form all contribute to the carbon dioxide breath test result. A drug that would be a useful substrate when the carbon dioxide breath test is used as a probe for changes in liver function should be at least 50% metabolized by demethylation, have a hepatic extraction ratio of 0.2–0.5, and be administered in a form that is rapidly absorbed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01059282
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  • 245
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    Effects of the rate and composition of fluid replacement on the pharmacokinetics and pharmacodynamics of intravenous furosemide (1986)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 14 (1986), S. 495-509 
    Details
    ISSN: 1573-8744
    Keywords: furosemide ; pharmacokinetics ; pharmacodynamics ; fluid replacement
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Effects of differences in the rate and composition of intravenous fluid replacement for urine loss on the pharmacokinetics and pharmacodynamics of furosemide were evaluated using the dog as a model animal. Each of six dogs received 8-hr constant intravenous infusion of 20 mg (15 mg used in one dog) of furosemide with 0% replacement (treatment I), 50% replacement (treatment II), and 100% replacement (treatment III) with lactated Ringer's solution, as well as with 100% replacement with 5% dextrose in water (treatment IV). Most pharmacokinetic parameters, such as plasma clearance, steady-state volume of distribution, mean residence time, and terminal half-life, were essentially the same in all four treatments. Renal clearances and urinary excretion rates of the drug in treatments II–IVwere essentially the same, but about 20% higher than those in treatment I.In spite of the similarities in kinetic properties, diuretic and/or natriuretic effects from furosemide were markedly different among the four treatments. For example, mean 10-hr urine outputs were 646, 1046, 3156, and 1976 ml and mean 10-hr sodium excretions were 87.0, 142, 383, and 97.2 mmole for treatments I–IV,respectively. Except for treatment III,diuresis and/or natriuresis were found to be time-dependent, generally decreasing with time until reaching a low plateau during later hours of infusion. The present findings also showed that (1)no fluid replacement and 100% replacement with 5% dextrose solution both produced the same degree of severe acute tolerance in natriuresis, indicating the insignificance of water compensation in tolerance development; (2)in treatment II,where neutral sodium balance was achieved, the development of acute tolerance in diuresis and natriuresis can mainly be attributed to negative water balance under this special condition; (3)at steady state the hourly diuresis and natriuresis could differ up to about ten times between treatments. Some implications for the kinetic/dynamic relationship or modeling, in the clinical use, and in the bioequivalence evaluation of dosage forms are discussed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01059657
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    Amiodarone pharmacokinetics. I. Acute dose-dependent disposition studies in rats (1986)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 14 (1986), S. 601-613 
    Details
    ISSN: 1573-8744
    Keywords: amiodarone ; pharmacokinetics ; dose-dependent ; rats
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Single intravenous bolus doses of amiodarone hydrochloride of 30, 60, 90 and 120 mg/kg were administered to male Sprague-Dawley rats to determine the effects of dose on amiodarone pharmacokinetics. Serial blood samples and total urine were collected over 48 hr and assayed for amiodarone and desethylamiodarone by HPLC. The blood amiodarone concentration-time curves for the four doses were best described by a triexponential equation with terminal half-lives (t 1/2γ ) ranging from 17 to 20 hr. Over the dose range studied, no changes in γ, t 1/2γ , or central compartment volume (Vc=1.2–1.4 L/kg) were observed. On the other hand, reductions in amiodarone clearance (CL and steady-state volume of distribution (V ss of 44% (17.7 to 10.0 ml/min per kg) and 50% (16.4 to 8.2 L/kg), respectively, were noted as the dose of amiodarone increased. The conversion of amiodarone to desethylamiodarone (fm was dose-independent and amounted to approximately 10% of each amiodarone dose. No amiodarone or desethylamiodarone was detected in the urine of any of the treated animals. The blood-to-plasma concentration ratio of amiodarone was concentration-independent and therefore did not account for the dose-dependent changes in Vss and CL observed. The data suggested that the dose-dependent changes noted were due to an alteration in the volume (s) of the peripheral tissue compartment(s).
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01067966
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    Analysis of pethidine disposition in the pregnant rat by means of a physiological flow model (1986)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 14 (1986), S. 381-395 
    Details
    ISSN: 1573-8744
    Keywords: pethidine ; rat ; physiological flow model ; pharmacokinetics ; pregnancy ; scale up ; opiates, GC-MS analytical method ; simulations
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The disposition of pethidine (meperidine) in the pregnant rat is described by means of a physiological flow model. The model includes arterial and venous blood, brain, fat, fetal, hepatic, intestinal, muscular, pulmonar, and renal tissues. The concentration-time profiles of pethidine calculated by the model are consistent with experimental data, except for the brain and renal tissues, where the model predicts initially higher concentrations. Simulations are carried out to further explore the contribution from different organs on the kinetics in blood and tissues. The tissue-to-blood partition coefficients vary over a range from 5 to 316, where fat has the lowest and liver the highest after a correction is made due to hepatic extraction. Rapid uptake occurs into highly perfused organs such as brain, kidneys, liver, and lungs, followed by fetus, intestines, muscle, and fat. Data indicate no marked membrane resistance to pethidine of the investigated organs, except for fetal tissues, but rather a perfusion-limited uptake. Simulations suggest that muscles and adipose tissue play an important role in the rat, becoming the major reservoir of drug during the intermediate and terminal elimination phase, respectively. Volume of distribution and the biological half-life agree with reported findings. Pethidine is subject to a high systemic blood clearance, which exceeds the total hepatic blood flow in the rat. No degradation of pethidine is found in blood, and therefore a pulmonary expression for pethidine clearance is added as a potential source of pethidine elimination. The elimination of pethidine after a single i.v. bolus dose is found to be dependent on simulated changes in cardiac output and hepatic blood flow. A simulation is performed with the scaled model to mimic the human concentration-time profiles in maternal blood and brain tissues and fetal tissue during repetitive doses of pethidine.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01059198
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    Saturable Processes Affecting Renal Clearance of Cefixime in Dogs (1986)
    Springer
    Pharmaceutical research 3 (1986), S. 150-155 
    Details
    ISSN: 1573-904X
    Keywords: renal clearance ; cephalosporin ; cefixime ; tubular reabsorption ; saturable protein binding ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The pharmacokinetics of cefixime, a new orally active cephalosporin, was studied after an intravenous dose of 50 mg/kg to four beagle dogs. Cefixime was shown to exhibit concentration dependent serum protein binding and saturable tubular reabsorption. The drug was excreted mainly in the urine, the net result of glomerular filtration and saturable tubular reabsorption. The experimental results were analyzed by model independent pharmacokinetic equations and with theoretical models describing renal clearance. Modification of the models, based on observed data, was proposed. The experimental methods employed and the pharmacokinetic approach offered in this study can be applied to drugs that exhibit concentration dependent protein binding and saturable renal elimination processes.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016309923717
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    The Effect of Amiodarone on Theophylline Pharmacokinetics in the Rat (1986)
    Springer
    Pharmaceutical research 3 (1986), S. 167-169 
    Details
    ISSN: 1573-904X
    Keywords: amiodarone ; theophylline ; pharmacokinetics ; drug interaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Amiodarone is an investigational antiarrhythmic agent which has been implicated in reducing the activity of the hepatic mixed-function oxidase system. To evaluate this effect further, two groups of six male Sprague–Dawley rats each received theophylline (6 mg/kg, iv) preceded by either normal saline or amiodarone HC1 (100 mg/kg, iv). Blood samples were obtained serially for a period of 6 hr and the sera were assayed for theophylline by high-pressure liquid chromatography (HPLC). In rats pretreated with amiodarone, a significant 45% reduction in the mean (± SD) systemic clearance [0.057 (0.010) vs 0.031 (0.004) liter/hr/kg, P 〈 0.001] and a greater than 100% increase in the mean elimination half-life [2.03 (0.46) vs 4.29 (0.71) hr, P 〈 0.001] of theophylline were observed. These data demonstrate an acute inhibitory effect of amiodarone on the hepatic microsomal enzyme system.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016366008696
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    Engineering Targeted In Vivo Drug Delivery. I. The Physiological and Physicochemical Principles Governing Opportunities and Limitations (1986)
    Springer
    Pharmaceutical research 3 (1986), S. 333-344 
    Details
    ISSN: 1573-904X
    Keywords: drug delivery, targeted ; prodrugs ; pharmacokinetics ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract A physiologically based model is presented to aid prediction of the pharmacological benefits to be derived from the administration of a drug as a targeted drug–carrier combination. An improvement in the therapeutic index and an increase in the therapeutic availability are the primary benefits sought. A measure of the former is obtained from the value of the drug targeting index, a newly derived parameter. Both the drug targeting index and the therapeutic availability are directly calculable. The minimum information needed for approximating both parameters is the candidate drug's total-body clearance and some knowledge of the target site's anatomy and blood flow. Drugs with high total-body clearance values that are known to act at target tissues having effective blood flows that are small relative to the blood flow to the normal eliminating organs will benefit most from combination with an efficient, targeted carrier. Direct elimination of the drug at the target site or at the tissue where toxicity originates dramatically improves the drug targeting index value. The fraction of drug actually released from the carrier at both target and nontarget sites can radically affect index values. In some cases a 1% change in the fraction of the dose delivered to the target can result in a 50% change in the drug targeting index value. It is argued that most drugs already developed have a low potential to benefit from combination with a drug carrier. The approach allows one to distinguish clearly those drugs that can benefit from combination with targeted in vivo drug carriers from those drugs that cannot.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016332023234
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    Influence of Malnutrition on the Disposition of Metronidazole in Rats (1986)
    Springer
    Pharmaceutical research 3 (1986), S. 352-355 
    Details
    ISSN: 1573-904X
    Keywords: malnutrition ; metronidazole ; pharmacokinetics ; rats ; metabolism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The influence of dietary protein deficiency on the disposition of metronidazole and its two major metabolites was examined in male Sprague–Dawley rats fed for 4 weeks on a 23% (control-) or a 5% (low-) protein diet ad libitum. Following an intravenous bolus dose of 10 mg/kg metronidazole hydrochloride, blood samples were obtained serially for a period of 24 hr after drug administration. Serum concentration–time data were analyzed by nonlinear least-squares regression, as well as noncompartmental techniques. The average mean residence time (MRT) was significantly prolonged by 48%, while the systemic clearance (Cl) was decreased by 42% in the protein-deficient rats. Since there was no alteration in the apparent steady-state volume of distribution (V ss), the mean harmonic half-life was increased from 2.9 to 5.0 hr in the protein-deficient rats. Although the percentage of metronidazole recovered as total drug in the urine over 24 hr was not significantly different between the two groups of animals, rats on a low-protein diet excreted a significantly smaller percentage of the administered dose as unchanged metronidazole (mean ± SD, 24.6 ± 3.8 vs 36.5 ± 12%) and a larger percentage (16.7 ± 2.6 vs 8.3 ± 1.8%) as the hydroxylated metabolite. No significant difference in the partial metabolic clearance of the hydroxylated metabolite of metronidazole was seen between the two groups of animals; however, there was a significant decrease in the renal clearance of metronidazole (1.45 ± 0.68 vs 0.55 ± 0.06 ml/min/kg) in the rats fed a low-protein diet. We conclude that the decreased clearance of metronidazole in protein deficiency is a result primarily of the decreased glomerular filtration rate, decreased biliary excretion, and/or increased net tubular reabsorption of metronidazole.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016433724142
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    Bioavailability of Propranolol After Oral, Sublingual, and Intranasal Administration (1986)
    Springer
    Pharmaceutical research 3 (1986), S. 108-111 
    Details
    ISSN: 1573-904X
    Keywords: propranolol ; intranasal ; sublingual ; absorption ; bioavailability ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The bioavailability of propranolol was compared after oral, sublingual, and intranasal administration in eight healthy male volunteers. Relative to the bioavailability after intranasal (in) administration, which was previously shown to be nearly complete (F relin = 100%), the sublingual (sl) administration of a standard 10-mg tablet gave a bioavailability of F relsl = 63 ± 22%, while the oral (or) administration yielded only F relor = 25 ± 8%. The serum concentration–time curves of propranolol after sublingual administration resembled those of a sustained-release preparation. This sustained-release phenomenon after the sublingual route is reflected in the mean residence times (MRTs) of propranolol in the body (MRTor = 5.7 ± 1.3 hr, MRTsl - 6.4 ± 1.3 hr, MRTin = 4.6 ± 1.0 hr; mean ± SD; N = 8). MRTs after sublingual administration were significantly longer than after the oral and the intranasal doses (P 〈 0.05 and P 〈 0.002, respectively).
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016345504153
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    Pharmacokinetics and Reversible Biotransformation of Sulfinpyrazone and Its Metabolites in Rabbits. I. Single-Dose Study (1986)
    Springer
    Pharmaceutical research 3 (1986), S. 173-177 
    Details
    ISSN: 1573-904X
    Keywords: sulfinpyrazone ; pharmacokinetics ; reversible metabolism ; single dose
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract In rabbits receiving sulfmpyrazone (SO) and the sulfide metabolite (S) in four separate experiments, the biotransformation of SO into S was found to be reversible, which resulted in approximately parallel terminal disposition profiles for the three major substances in plasma, i.e., SO, S, and the p-OH-sulfide (OH-S). However, differences in disposition kinetics were observed between the intravenous and the peroral administration. The formation of OH-S was independent of both the administered compound and the administration route. The results obtained in the present studies, the previously documented enterohepatic recirculation, and the formation of S by hindgut flora may have implications for studies on sulfinpyrazone, which has been used as an antithrombotic agent.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016370209604
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    Pharmacokinetics and Reversible Biotransformation of Sulfinpyrazone and Its Metabolites in Rabbits. II. Multiple-Dose Study (1986)
    Springer
    Pharmaceutical research 3 (1986), S. 178-183 
    Details
    ISSN: 1573-904X
    Keywords: sulfinpyrazone ; pharmacokinetics ; reversible metabolism ; multiple dose
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract In crossover studies rabbits were given sulfmpyrazone (SO) and its sulfide metabolite (S) perorally once daily (10 mg/kg) for 5 days. Comparison of the pharmacokinetic parameters obtained after the first and the fifth dose indicates that repeated dosing does not alter disposition kinetics of both SO and S, except that in dosing with S the observed terminal half-life for S is significantly reduced, from 4.59 ± 0.55 to 2.86 ± 0.6 hr (SD). In other studies rabbits were given higher single doses (15, 25, and 50 mg/kg) perorally and comparison was made between these dose sizes and the first dose (10 mg/kg) of multiple administration with S. Some kinetic parameters tended to be altered in a nonlinear fashion, and greater intersubject variations were observed because of the dose increase, while oxidation to SO or p-hydroxylation to OH-S from S was not significantly altered.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016322326443
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    Pharmacoclinical data on high dose medroxyprogesterone acetate in advanced breast cancer (1986)
    Springer
    Breast cancer research and treatment 8 (1986), S. 161-163 
    Details
    ISSN: 1573-7217
    Keywords: medroxyprogesterone acetate ; pharmacokinetics ; response ; toxicity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01807705
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    Phase I clinical and pharmacokinetic study of bisantrene in refractory pediatric solid tumors (1986)
    Springer
    Investigational new drugs 4 (1986), S. 149-153 
    Details
    ISSN: 1573-0646
    Keywords: bisantrene ; Phase I ; pharmacokinetics ; pediatric solid tumors
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Fourteen patients with pediatric malignant solid tumors, median age 15 years, received 22 courses of bisantrene in a Phase I study. Dosage escalations ranged from 10 to 120 mg/m2 daily for 5 consecutive days. Toxicity included myelosuppression and phlebitis. A sensitive (detection limit of 2 ng/ml) and specific HPLC method was developed to quantitate bisantrene in patient's plasma and urine. Peak plasma concentrations at the end of 60 minute infusions ranged from 568 ng/ml at 10 mg/m2 to 6800 ng/ml at the 100 mg/m2 dosage. The elimination half life (T 1/2β) averaged about 10 hours but increased to 20 hours in a patient with liver disease. Only 2.4–10% of the bisantrene dose was eliminated in the urine suggesting that the liver may be the major route of elimination for this antineoplastic anthracene derivative.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00194594
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