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  • Electronic Resource  (89)
  • 2020-2022
  • 1985-1989
  • 1975-1979  (89)
  • 1979  (56)
  • 1977  (33)
  • pharmacokinetics
  • 1
    Electronic Resource
    Electronic Resource
    Relationship between plasma concentration and effect of dantrolene sodium in man (1979)
    Springer
    European journal of clinical pharmacology 16 (1979), S. 203-209 
    Details
    ISSN: 1432-1041
    Keywords: dantrolene sodium ; spasticity ; twitch tension ; dose response ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Dantrolen sodium is a muscle relaxant, which is used in the treatment of spasticity. Although it is given chronically, little is known about its pharmacokinetic behaviour. The relationship between the effect of a single oral dose of dantrolene sodium and its plasma concentration in healthy volunteers was studied by measuring the effect on the twitch tension, and in spastic patients on the decrease in muscle hypertonia. On the twitch tension dantrolene gave a depression of 49.1±9.4% (±SD) within 1.15 and 3.45 h after ingestion of 100 mg. The mean maximal plasma concentration was 1.24±0.32 µg/ml (±SD). The effect and the plasma concentration were correlated. No relationship between the plasma concentration of dantrolene sodium and its effect could be established in patients, although definite activity in 6 out of 7 patients was observed after a single oral dose of 100 mg, and plasma concentration of dantrolene sodium greater than 0.3 µg/ml were consistently associated with better results than placebo treatment in 6 out of 7 patients.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00562062
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  • 2
    Electronic Resource
    Electronic Resource
    Pharmacokinetic model based on circulatory transport (1979)
    Springer
    European journal of clinical pharmacology 16 (1979), S. 287-293 
    Details
    ISSN: 1432-1041
    Keywords: linear system theory ; perfusion model ; cardiac output ; pulmonary extraction ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Assessment of pharmacokinetics in terms of circulatory drug transport is proposed using the methods of linear system theory. In this model-independent approach drug distribution and disposition are characterized by the total extraction ratio, the mean residence time in the body and the volume of distribution at steady state. In analyzing concentration(c)-time(t) data, the procedure requires calculation only of the areas under the c(t)-and c(t)×t-curves to estimate kinetic parameters, and for prediction of the steady state concentration following continuous infusion or multiple doses. Pulmonary clearance of drugs is included in the theory.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00608408
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  • 3
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of bromocriptine during continuous oral treatment of Parkinson's disease (1979)
    Springer
    European journal of clinical pharmacology 15 (1979), S. 275-280 
    Details
    ISSN: 1432-1041
    Keywords: Parkinson's disease ; bromocriptine ; pharmacokinetics ; plasma concentration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The plasma kinetics of bromocriptine (BCT), a long-acting dopamine agonist, was studied in twelve patients with Parkinson's disease, using a newly developed gas chromatographic method of analysis. Each patient received BCT for at least three weeks in a constant but different dose regimen. Concomitant treatment with 1-DOPA was not allowed. During a 6-day hospitalization period, a blood sample was taken immediately before the afternoon dose at 14.00 h (Cmin) to determine the steady-state level. On the 6th day blood samples were collected every hour during two 8 h dose intervals. The results showed a significant correlation between the mean values of the AUC and the Cmin. First order elimination kinetics appeared to be followed by BCT, at least for the plasma concentrations commonly found. Considerable inter-individual variation was demonstrated both for the dose/plasma concentration ratio and for calculated plasma clearances. No serious side-effects were observed during the investigation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00618517
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  • 4
    Electronic Resource
    Electronic Resource
    Indobufen (K 3920), a new inhibitor of platelet aggregation: Effect of food on bioavailability, pharmacokinetic and pharmacodynamic study during repeated oral administration to man (1979)
    Springer
    European journal of clinical pharmacology 15 (1979), S. 329-333 
    Details
    ISSN: 1432-1041
    Keywords: indobufen ; platelet aggregation ; food effect on bioavailability ; repeated administration ; pharmacodynamics ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of food on bioavailability of indobufen tablets was investigated in 6 healthy volunteers. Subsequently, the same subjects took 100 mg b.i.d. for 7 days. Plasma levels and urinary excretion of indobufen were determined by GLC. Platelet aggregation induced by several concentrations of adrenaline was determined turbidimetrically at various times after the first and last doses. The absorption of indobufen tablets was not substantially impaired by the presence of food in the GI tract, although peak plasma levels and AUCs were slightly reduced after food. Pharmacokinetic analysis of plasma and urinary levels of indobufen did not indicate any change in drug disposition after repeated dosing. Adrenaline-induced platelet aggregation was markedly inhibited for up to 12 h after the first dose and the intensity and duration of this effect did not change after repeated administration. A twice-daily dosing appears suitable for clinical trials.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00558436
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  • 5
    Electronic Resource
    Electronic Resource
    Clofibrate disposition in renal failure and acute and chronic liver disease (1979)
    Springer
    European journal of clinical pharmacology 15 (1979), S. 341-347 
    Details
    ISSN: 1432-1041
    Keywords: clofibrate ; chlorophenoxyisobutyric acid ; disposition ; hepatitis ; cirrhosis ; renal failure ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The disposition of clofibrate over 96 hours was observed following single oral dose in six patients with acute viral hepatitis, six patients with liver cirrhosis, seven patients with renal insufficiency, and six control subjects. No parameter of the disposition of CPIB (active form of clofibrate) was significantly altered in acute hepatitis. In liver cirrhosis, the mean plasma half-life was unchanged compared to controls (20.9 vs. 17.5 h), but plasma clearance of the non-protein bound drug was reduced (115 vs. 243 ml×min−1), plasma protein binding was reduced (92.8 vs. 97.2 percent), and the apparent volume of distribution was increased (0.20 vs. 0.141×kg−1). In renal insufficiency plasma half-life was prolonged 2 to 6-fold, depending on the degree of renal impairment. Total plasma clearance (3.4 vs. 7.1 ml×min−1) and plasma clearance of the unbound drug (81 vs. 243 ml×min−1 were reduced in patients with renal failure, the clearance of the unbound drug being inversely correlated with the serum creatinine concentration. Renal failure was also associated with decreased protein binding and an increased volume of distribution of CPIB, and with reduced urinary excretion of CPIB and its glucuronide metabolite. The dose of clofibrate should be halved in patients with cirrhosis. In renal insufficiency, the dose should be adjusted according to the individual serum creatinine level: only 10 to 15% of the usual weekly dose should be given in complete renal failure.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00558438
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  • 6
    Electronic Resource
    Electronic Resource
    The protein binding of methotrexate by the serum of normal subjects (1979)
    Springer
    European journal of clinical pharmacology 15 (1979), S. 363-366 
    Details
    ISSN: 1432-1041
    Keywords: methotrexate ; protein binding ; ultrafiltration ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The protein binding of methotrexate by serum from eight normal volunteers was assessed by continuous ultrafiltration at pH 7.4 and 37°C. Methotrexate concentrations were measured by radioimmunoassay and the data analysed by the method of Scatchard. The major binding protein was albumin which bound 87.3% of the drug in serum. Analysis of the Scatchard plots indicated two distinct groups of binding sites. Class I was found to have 0.16±0.05 (S D) binding sites with an intrinsic association constant of 71.15±35.98 (S D)×104 M−1: Class II had 2.01±0.93 (S D) binding sites and an affinity of 0.18±0.15×104 M−1. No great change in the percentage of methotrexate bound occurred until the total concentration of the drug exceeded 50 µMol 1−1.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00558441
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  • 7
    Electronic Resource
    Electronic Resource
    Timolol pharmacokinetics and effects on heart rate and blood pressure after acute and chronic administration (1979)
    Springer
    European journal of clinical pharmacology 16 (1979), S. 243-249 
    Details
    ISSN: 1432-1041
    Keywords: timolol ; beta blockade ; pharmacokinetics ; pharmcodynamics ; acute administration ; chronic administration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics and effects of various oral doses of timolol administered either acutely or after chronic medication for 7 days were studied in healthy volunteers. After acute administration of timolol maximum plasma concentrations were attained within 1–2 h and thereafter declined exponentially with time. The mean apparent half-life of elimination from plasma was 2.5 h and was independent of dose. Area under the plasma concentration-time curve (AUC) was proportional to the orally administered dose. Plasma concentrations, apparent elimination half-life and AUC were not altered after one week of chronic administration. The effect of timolol on heart rate and blood pressure response to three sequentially increasing ‘steady state’ work loads were studied. After acute administration of timolol maximum reduction of systolic blood pressure, resting heart rate, and the different parameters of the work-heart rate (or blood pressure) relationships were produced by 5 mg timolol. Increasing the dose prolonged the duration over which these variables were reduced. The relationship between timolol plasma concentration and inhibition of different parameters of the exercise response was hyperbolic with half maximum inhibition at concentrations of about 3–4 ng/ml of timolol and maximum inhibition above 30 ng/ml. Maximum drug effects and duration of action of timolol on the different variables were similar after acute and chronic administration.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00608402
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  • 8
    Electronic Resource
    Electronic Resource
    Pharmacokinetic and pharmacodynamic interactions of diazepam with different alcoholic beverages (1979)
    Springer
    European journal of clinical pharmacology 16 (1979), S. 263-270 
    Details
    ISSN: 1432-1041
    Keywords: diazepam ; alcoholic beverages ; plasma level ; pharmacokinetics ; co-ordination skills ; red wine ; white wine ; whisky
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Twenty paid healthy students ingested diazepam 10 mg 30 min after the administration of ethanol 0.8 g/kg. The alcoholic beverage used was varied in randomized double-blind experiments, which were repeated at one-month intervals. Psychomotor performance, plasma diazepam, and alcohol concentration in breath were measured 30, 60, 90 min and 2, 3, 4, 6 and 24 h after the ingestion of diazepam. Beer and white wine elevated the plasma level of diazepam and the effect lasted for up to 2 h. Whisky elevated the diazepam level for 90 min. Red wine did not affect it significantly. The alcohol-diazepam combination impaired tracking skills and oculomotor co-ordination and enhanced nystagmus, more than diazepam alone. Red wine produced a breath alcohol concentration higher than after white wine. More nystagmus was recorded after red wine and diazepam, although white wine led to a higher plasma diazepam concentration. It appears that simultaneous ingestion of alcohol and diazepam accelerates the absorption of diazepam. This pharmacokinetic alteration may not contribute much to the combined psychomotor effects of diazepam and alcohol, which were mainly due to pharmacodynamic interaction at receptor level.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00608405
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  • 9
    Electronic Resource
    Electronic Resource
    Analysis of the pharmacokinetics of lithium in man (1979)
    Springer
    European journal of clinical pharmacology 16 (1979), S. 271-277 
    Details
    ISSN: 1432-1041
    Keywords: lithium ; litarex ; single dose ; multiple dose ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary An analysis of the single and multiple dose pharmacokinetics of lithium in 7 healthy volunteers is presented. A solution of lithium chloride was administered in single dose experiments and the same solution and a sustained release preparation were employed in multiple dose experiments, which were carried out at steady state. A fixed dose of 24 mmol was used in the single dose experiments and in the subsequent multiple dose experiments in the same subjects the same dose was administered once daily for a week. Distinct two-compartment characteristics were found, with a mean disposition rate constant (β) of 0.035 h−1±0.010 SD, corresponding to a mean biological half-life of about 19.8 h. The mean half-time of the distributory α-phase was about 1.15 h. The absorption of lithium from an orally administered solution took place with a half-time of about 0.15 h in the single dose experiments. The apparent volume of distribution of the central compartment (Vc) was 0.307 1 kg−1±0.046 SD, less than half that of Vde at equilibrium. Vdβ (Vdarea) was 0.8291 kg−1±0.184 SD and mean total body clearance was 27.6 ml kg−1 h−1±4.7 SD.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00608406
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  • 10
    Electronic Resource
    Electronic Resource
    Kinetics of canrenone after single and multiple doses of spironolactone (1979)
    Springer
    European journal of clinical pharmacology 16 (1979), S. 255-262 
    Details
    ISSN: 1432-1041
    Keywords: spironolactone ; canrenone ; fluorimetry ; high performance liquid chromatography ; linear kinetics ; saturation kinetics ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In Study I 20 normal volunteers received a single oral dose of spironolactone 100 mg. In Study II a further 20 normal volunteers were given first spironolactone 100 mg b.i.d. and subsequently spironolactone 100 mg once a day for a further 4 days. In Study III 5 normal subjects were given a single dose of spironolactone 500 mg. The concentration of canrenone in serum was determined both by fluorimetry and HPLC for 0–48 h in Study I, 120–168 h in Study II and 0–36 h in Study III. The total AUCs after the single 100 mg dose did not differ from the AUCs within the dosing interval during steady state. The half-lives of the terminal log-linear phases were almost identical (14.99±0.80 h and 15.69±0,80 h) when determined by fluorimetry, and were sligthly, but significantly (p〈0.01), longer when determined by HPLC — 20.14±1.62 and 18.71±1.04. The mean ratio of the specific AUC determined by HPLC and the fluorimetrically determined AUC was 0.3 after the single 100 mg dose. It did not differ from the corresponding value during steady state (0.34). In contrast, the ratio after the single 500 mg dose was approximately 50% higher. Fluorimetrically determined AUCs after 100 and 500 mg doses did not show dose-proportionality in contrast to the HPLC-determined AUCs. It was concluded that Canrenone contributes much less to the conventional fluorimetric determination than was previously assumed. It may not provide more than 1/10 and 1/4 of the antimineralocorticoid activity of spironolactone after single dose and multiple doses, respectively. Whereas linear kinetics apply after single and multiple 100 mg doses of spironolactone, after 500 mg saturation kinetics must be assumed with respect to metabolism. Thus, in bioavailability studies high doses of spironolactone should be avoided. For such studies the fluorimetric assay seems to be the appropriate bioanalytical method in spite of its lower specificity.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00608404
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  • 11
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of quinidine related to plasma protein binding in man (1979)
    Springer
    European journal of clinical pharmacology 15 (1979), S. 187-192 
    Details
    ISSN: 1432-1041
    Keywords: quinidine ; plasma protein binding ; pharmacokinetics ; man
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The disposition and plasma protein binding of quinidine after intravenous administration were studied in 13 healthy subjects. Plasma protein binding, expressed as the fraction of quinidine unbound ranged from 0.134–0.303 (mean 0.221). Elimination rate constant (β) varied from 0.071 to 0.146 h−1 (mean 0.113), and apparent volume of distribution (Vβ) varied from 1.39–3.20 l · kg−1β (mean 2.27). Total body clearance was 2.32–6.49 ml min−1 · kg−1. There was a positive linear correlation between the plasma fraction of unbound quinidine and both Vβ (r=0.885, p〈0.01) and total body clearance (r=0.668, p〈0.05). No significant correlation existed between the fraction of unbound quinidine in plasma and the elimination rate constant. The results show that both the apparent volume of distribution and total body clearance of quinidine are proportional to the unbound fraction in plasma. This implies that the total plasma concentration of quinidine at steady state will change with alterations in plasma binding, whilst the concentration of unbound compund and its elimination rate will remain unaffected.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00563104
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  • 12
    Electronic Resource
    Electronic Resource
    Oral absorption of cimetidine and its clearance in patients with renal failure (1979)
    Springer
    European journal of clinical pharmacology 15 (1979), S. 153-157 
    Details
    ISSN: 1432-1041
    Keywords: cimetidine ; renal failure ; elimination half life ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The plasma concentration curve after a single oral dose of cimetidine 200 mg was followed in 27 patients with varying degrees of chronic renal failure (creatinine clearance 1–52 ml/min) and in 46 patients with normal serum creatinine. Compared to the latter patients, the plasma concentration was higher and the elimination rate was slower in all uraemic subjects, including a group with moderate renal impairment. The preliminary recommendations of dosage for patients with a creatinine clearance below 5 ml/min, and for patients on regular haemodialysis, is cimetidine 200 mg every 12 h, 5–15 ml/min 200 mg every 12 to 8 h, 15–30 ml/min 200 mg every 8 h and 30–52 ml/min 200 mg every 6 h.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00563098
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  • 13
    Electronic Resource
    Electronic Resource
    Human pharmacokinetics of nitrazepam: Effect of age and diseases (1979)
    Springer
    European journal of clinical pharmacology 15 (1979), S. 163-170 
    Details
    ISSN: 1432-1041
    Keywords: nitrazepam ; epilepsy ; age ; disease ; plasma concentration ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Plasma concentrations of nitrazepam were measured by gas-liquid chromatography in: young healthy volunteers, in geriatric and psychiatric patients and in epileptic children. The disposition of nitrazepam was described in terms of a two-compartment open model. After a single oral dose of nitrazepam 5 mg the most prominent differences between the experimental groups were in the β-phase half-life-mean 29 h in the young volunteers and 40 h in geriatric patients, and in the apparent volume of distribution during the β-phase of 2.4 vs 4.8 l/kg. Total plasma clearance and the average steady state concentration in both groups were equal. The plasma level rose at a rate proportional to the β-phase half-life, and so, they were achieved more rapidly in the young than in the old subjects (3.5 vs 7.5 d). No change in steady-state level or in the half-life of nitrazepam were found during long term treatment, which indicates lack of enzyme induction or inhibition. In 95% of the epileptic children with a good to fair clinical response, the plasma concentration of nitrazepam was 40–180 ng/ml (mean 114 ng/ml). As all of the patients were on combined antiepileptic therapy, no attempt was made to correlate plasma level with therapeutic response.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00563100
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  • 14
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of clorazepate in pregnant and non-pregnant women (1979)
    Springer
    European journal of clinical pharmacology 15 (1979), S. 175-180 
    Details
    ISSN: 1432-1041
    Keywords: clorazepate ; nordiazepam ; pregnancy ; pharmacokinetics ; intramuscular injection
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A single dose of clorazepate 20 mg was injected i.m. in 7 pregnant and 7 non-pregnant women. Blood samples were collected for one week, and urine was collected for 24 h after the dose. The concentrations of clorazepate and its metabolite nordiazepam were determined by electron capture gas liquid chromatography. There was no difference between the two groups on physical examinations. Clorazepate was rapidly absorbed and the peak concentration was reached within 2h. Mean pharmacokinetic parameters for clorazepate were absorption half life 0.77h in pregnant women and 0.56h in non-pregnant women; elimination half life 1.3h in pregnant women and 2.0h in non-pregnant women; volume of distribution: 0.43 l · kg−1 in the pregnant women and 0.33 l · kg−1 in non-pregnant women. Nordiazepam reached its peak concentration within 12h after dosing; its mean half life of elimination was 180h in pregnant women and 60h in non-pregnant women. Within 24h, 1.3% of the clorazepate was recovered in urine from pregnant women and 7% in urine from the non-pregnant women.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00563102
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  • 15
    Electronic Resource
    Electronic Resource
    Blood level of cimetidine in relation to age (1979)
    Springer
    European journal of clinical pharmacology 15 (1979), S. 257-261 
    Details
    ISSN: 1432-1041
    Keywords: cimetidine ; H2-receptor antagonist ; aging ; single dose ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The blood level versus time curve for unchanged cimetidine after a 200 mg oral dose has been determined in 20 apparently healthy subjects, ranging from 22 to 84 years of age. A significant relationship between the area under the curve (AUC) and age was found (r=0.81; P〈0.001). The peak concentrations of cimetidine were significantly inversely related to body weight (r=−0.71; P〈0.001). The age-related increase in bioavailability of oral cimetidine, as measured by AUC, was probably due to decreased total clearance of the drug, which resulted from the opposed changes (by themselves not significant) of distribution volume towards a decrease and of half-life towards an increase with age. Reduction in the standard oral dose of cimetidine by one third to one half should be feasible in the elderly without loss of efficacy, and it may be advisable in order to obviate extreme individual responses that may occur in this population.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00618514
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  • 16
    Electronic Resource
    Electronic Resource
    Absolute bioavailability of chlorthalidone in man: A cross-over study after intravenous and oral administration (1979)
    Springer
    European journal of clinical pharmacology 15 (1979), S. 35-50 
    Details
    ISSN: 1432-1041
    Keywords: chlorthalidone ; pharmacokinetics ; oral and i.v. doses ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Seven normal human volunteers each received a constant-rate infusion of chlorthalidone for 2 h, and the same (commonly 50 mg) single oral dose on separate occasions. The concentration of unchanged chlorthalidone was analyzed over a 100 to 220 h period in plasma, red blood cells, urine and faeces after both dosage forms. A three compartment model was required to describe the intravenous plasma concentrations in five of the subjects. A two compartment model sufficed to account for the decay of the oral plasma concentrations in all seven subjects. The mean plasma t1/2 after i.v. dosing was 36.5 h (±10.5 SD), and the mean plasma t1/2 after oral doses was 44.1 h (±9.6 SD). The mean red blood cell concentration t1/2 after i.v. doses was 46.4 h (±9.9 SD), and the mean red blood cell t1/2 after the oral doses was 52.7 h (±9.0 SD). The shorter i.v. half-live was not equally manifest in all subjects, being mainly apparent in three of them. In all cases the urinary excretion rate plots were parallel to the plasma concentration curves. As the faster decay after i.v. administration was not accompanied by increased renal clearance, the difference must have been due to non-renal mechanism. The mean total of 65.4 (±8.6 SD) % of the intravenous dose was excreted in urine over infinite time, whereas the mean total excretion after the oral dose was 43.8 (±8.5 SD) %. Faecal excretion ranged from 1.3–8.5% of dose in the i.v. study to 17.5–31.2% of dose in the oral study. The sum of the amounts present in urine plus faeces pointed strongly to an important metabolic route of elimination of chlorthalidone. Bioavailability estimates (F) from three sets of data were — a mean F of 0.61 from plasma concentrations, 0.67 from urinary excretion measurements and 0.72 from the erythrocyte concentrations. Simulations with a non-linear model indicated lesser validity of the estimate from erythrocyte concentrations. It was concluded that the average of plasma and urine data, F=0.64, yielded the best estimate of the oral availability of chlorthalidone 50 mg in man.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00563556
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  • 17
    Electronic Resource
    Electronic Resource
    Disposition of guanethidine during chronic oral therapy (1979)
    Springer
    European journal of clinical pharmacology 15 (1979), S. 121-125 
    Details
    ISSN: 1432-1041
    Keywords: guanethidine ; chronic therapy ; urinary excretion ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The plasma level and urinary excretion rate of guanethidine have been measured in 30 patients during oral maintenance therapy, and in 5 patients following discontinuation of therapy. A significant correlation was found between the daily average urinary excretion and the maintenance dose, although wide interindividual variation was noted among patients maintained on the same dose. A statistically significant correlation was also observed between the area under the plasma level curve during the dose interval and the oral maintenance dose. After discontinuation of chronic therapy, the half-life of 1.5 days of the initial phase of elimination was essentially in agreement with the half-life of almost 2 days determined in acute studies. In addition, a second phase of elimination with a half-life of 4 to 8 days was observed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00609875
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  • 18
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of the placental transfer and distribution of clorazepate and its metabolite nordiazepam in the feto-placental unit and in the neonate (1979)
    Springer
    European journal of clinical pharmacology 15 (1979), S. 181-185 
    Details
    ISSN: 1432-1041
    Keywords: clorazepate ; nordiazepam ; pregnancy ; placental transfer ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Clorazepate 20mg was given i. m. to 49 mothers during the first stage of labour. The elimination of the drug was studied in 27 newborns produced by these mothers. The same dose was given to 13 women who underwent amniocentesis and to 7 women who were breast-feeding. “Total nordiazepam”, i.e. the sum of clorazepate and its metabolite nordiazepam, was determined by gas-liquid chromatography in maternal blood, umbilical cord blood (both arterial and venous), amniotic fluid and in milk. Clorazepate was found to cross the placental barrier slowly, but nordiazepam was transferred more rapidly. Nordiazepam was found in the milk and in the blood of neonates after breast-feeding had started.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00563103
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  • 19
    Electronic Resource
    Electronic Resource
    Disposition pharmacokinetics of bezafibrate in man (1979)
    Springer
    European journal of clinical pharmacology 16 (1979), S. 31-38 
    Details
    ISSN: 1432-1041
    Keywords: bezafibrate ; hyperlipoproteinemia ; bioavailability ; pharmacokinetics ; GC-MS
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The disposition kinetics of bezafibrate, a newly developed drug of great lipid-lowering potency, were investigated in normal male subjects. Five male volunteers received14C-labelled bezafibrate orally in solution, and a further 10 were given the same dose (300 mg) of un-labelled drug as tablets. The concentration of bezafibrate in serum and urine from the latter was determined by GC, and in the former total radioactivity in serum, urine and feces was followed for 48 h, and urinary excretion products were analysed by TLC and GC-MS. Rapid absorption from the gastrointestinal tract led to peak serum levels 30 min and 2 h after administration of solution and tablets, respectively. Since approximately 95% of the administered14C-bezafibrate was excreted in urine within 48 h, and almost all the remainder was detected in feces, absorption can be regarded as complete after administration in solution. The relative optimal bioavailability from the tablets was also complete, since in both cases approximately 50% of the administered dose was detected as unchanged bezafibrate in urine within 24 h by GC in the tablet study, and by TLC in the solution study. Of the decomposition products, more than 20% of the dose was present as glucuronides and the remainder consisted of several more polar compounds, one of which was identified as a hydroxyderivative of bezafibrate. Since the apparent halflife of bezafibrate in serum was 2.1 h, this new drug possesses favourable pharmacokinetic features: rapid and complete absorption, even from tablets, combined with a conveniently short half-life, and clearance which is half renal (56 ml/min) and half metabolic (43 ml/min), giving a total clearance of 99 ml/min.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00644963
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  • 20
    Electronic Resource
    Electronic Resource
    Pharmacokinetic, bioavailability and pharmacodynamic study of indobufen (K 3920), an inhibitor of platelet aggregation, after a single dose in man (1979)
    Springer
    European journal of clinical pharmacology 15 (1979), S. 323-327 
    Details
    ISSN: 1432-1041
    Keywords: indobufen ; platelet aggregation ; single dose ; bioavailability ; pharmacodynamics ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Six healthy volunteers received single iv and oral doses of 2-[p-(1-oxo-2-isoindolinyl)phenyl] butyric acid 100 mg (indobufen; K 3920), an inhibitor of platelet aggregation. Plasma levels and urinary excretion of the drug were determined by GLC. Collagen-induced platelet aggregation was assessed turbidimetrically at various intervals after administration. The plasma half-life of the drug was 7–8 h and more than 70% of the administered dose was recovered within 48 h in urine, as unchanged drug and as the glucuronide of indobufen. After oral administration of tablets of two different formulations, the drug was completely absorbed, but one formulation showed faster absorption. The maximal inhibitory effect on platelet aggregation was observed 1 to 4 h after iv administration, and it had decreased by 8 h. After tablets, peak effect and the time of the peak were similar, but activity was significantly prolonged, in accordance with the higher plasma levels found at 8 h. The data suggest that the effect of indobufen on platelets is reversible, and that for this drug platelets behave as a compartment that slowly equilibrates with plasma.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00558435
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  • 21
    Electronic Resource
    Electronic Resource
    Cyclobarbital as a test substance for oxidative drug metabolism in man. Findings in neuropsychiatric patients (1979)
    Springer
    European journal of clinical pharmacology 15 (1979), S. 433-441 
    Details
    ISSN: 1432-1041
    Keywords: cyclobarbital ; barbiturates ; pharmacokinetics ; drug interaction ; volunteers ; patients
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The disappearance of cyclobarbital from plasma has been followed in healthy volunteers and in neurological and psychiatric patients after oral administration of one tablet of Phanodorm®, containing cyclobarbital calcium 200 mg. Plasma levels were measured by a thin-layer chromatographic method with in situ densitometry. The average t1/2 in healthy female and male volunteers was 13.3 h, and with the assumption of complete availability a mean distribution coefficient of 0.69 l/kg−1 and a clearance of 40.4 ml/min−1 were calculated. Repeated experiments in seven volunteers revealed good reproducibility of all values. When the healthy volunteers were combined with a group of untreated epileptics, a dependence of t1/2 and of the apparent volume of distribution on age was found, while clearance did not change with increasing age (range 17–54 years). Long half-lives caused by low clearance values were observed in several individuals with moderate obesity. No consistent change in cyclobarbital kinetics followed acute exposure of volunteers to alcohol or on treatment of neurological patients with carbamazepine. Patients under treatment with perazine exhibited more or less normal kinetic values. In terms of drug interaction, cyclobarbital differs from phenazone in several respects, and so it may prove a useful additional substance for measurement of the rate of drug oxidation in humans.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00561744
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  • 22
    Electronic Resource
    Electronic Resource
    Lorcainide infusion in the treatment of ventricular premature beats (VPB) (1979)
    Springer
    European journal of clinical pharmacology 16 (1979), S. 1-6 
    Details
    ISSN: 1432-1041
    Keywords: lorcainide ; ventricular premature beats ; plasma levels ; pharmacokinetics ; side effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The plasma level and antiarrhythmic effect of lorcainide (R 15889) have been investigated in 15 patients with ventricular premature beats (VPB). Therapy was initiated with an intravenous dose of 1.9 mg/kg given over 10 min, followed by a constant infusion of 0.18 mg/kg/h for 24 h. In 8 patients the corresponding doses were increased to 2 mg/kg and 0.27 mg/kg/h. After the intravenous doses patients were treated orally with 100 mg tid for 6–7 days. The two dosage regimens were selected so as to achieve theoretical steady-state plasma levels (css) of 200 and 300 ng/ml, respectively. The combined intravenous treatment approached (181 ± 6.8 ng/ml and 273±28.5 ng/ml, respectively) the desired css within 2 to 4 h. During the oral administration, the minimal plasma concentrations following the lower intravenous dose (184±18 ng/ml) were significantly (p=0.0001) lower than after the higher intravenous dose (264±20.5 ng/ml). The dealkylated metabolite of lorcainide was not detectable after the intravenous doses, but it accumulated during oral treatment, when its concentration exceeded that of the parent compound. In 5 of the 7 patients receiving the lower dose VPB were effectively reduced. However, in only 4 of the 8 patients on the higher dosage schedule could a significant antiarrhythmic effect be demonstrated. In addition, side effects were observed in 6 of the subjects.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00644958
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  • 23
    Electronic Resource
    Electronic Resource
    Single and chronic dose pharmacokinetic studies of sodium valproate in epileptic patients (1979)
    Springer
    European journal of clinical pharmacology 16 (1979), S. 23-29 
    Details
    ISSN: 1432-1041
    Keywords: valproate ; epilepsy ; pharmacokinetics ; drug interaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In four refractory epileptic patients, peak plasma levels of sodium valproate occurred within 1.5 to 3 h after a single oral dose of valproate and the decline in plasma levels followed a monoexponential course with a t1/2 of 11.4 ± 0.1 h. The mean value for apparent volume of distribution was 0.176 ± 0.013 l/kg and for total plasma clearance 0.0106 ± 0.0009 l/h/kg. Steady state plasma levels were predicted using the method of superposition utilizing pharmacokinetic parameters determined following a single dose of valproate and were 78–123% of the predicted values for two patients receiving valproate alone, and 37–64% of the predicted values for the two patients receiving carbamazepine in addition to valproate. In a further group of 20 patients the mean daily doses of valproate for 8 patients receiving valproate alone (25.4 ± 4.9 mg/kg) was significantly less than those for the 12 patients receiving concomitant anticonvulsant therapy (41.6 ± 12.3 mg/kg) (p〈0.005). In addition, the steady state predose plasma levels of valproate were significantly higher in the valproate alone patients (90.3 ± 8.7 µg/ml) compared to the patients receiving additional anticonvulsants (75.3 ± 13.8 µg/ml) (p〈0.01). The higher dose requirements of valproate and lower predose and steady state plasma levels for those patients on multiple anticonvulsants indicate an interaction between valproate and other anticonvulsants.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00644962
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  • 24
    Electronic Resource
    Electronic Resource
    Absolute bioavailability of quinidine in two sustained release preparations (1979)
    Springer
    European journal of clinical pharmacology 16 (1979), S. 45-48 
    Details
    ISSN: 1432-1041
    Keywords: quinidine ; slow release formulation ; pharmacokinetics ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The bioavailability of quinidine in two sustained release preparations A and B has been compared in three females and three males with i.v. administration of quinidine. The initial rate of oral absorption did not differ between the two drug preparations; the peak concentration was observed after 4 h both for A and B, but was significantly higher after B. A slower decrease in plasma concentration was observed after preparation A than B. Absolute bioavailability did not differ significantly between A (median value 78.4%) and B (median 87.1%). Drug absorption in vivo was in good agreement with the results of in vitro dissolution tests on both preparations. The slower decrease in plasma concentration found for the new sustained release form of quinidine should be of clinical advantage.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00644965
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  • 25
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of cephacetrile in patients undergoing haemodialysis (1979)
    Springer
    European journal of clinical pharmacology 16 (1979), S. 49-52 
    Details
    ISSN: 1432-1041
    Keywords: cephacetrile ; haemodialysis ; pharmacokinetics ; renal failure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of cephacetrile were studied after its administration as a single i.v. bolus injection of 15 mg/kg body weight to 11 patients with terminal renal inpairment undergoing haemodialysis for 6 h. A two-compartment kinetic model was used to describe the biphasic decrease in plasma concentration. The quantities of antibiotic in the central and peripheral compartments, and the amounts eliminated, were calculated for different times. During haemodialysis sessions, the average pharmacokinetic parameters of cephacetrile determined at the dialyser input were: α=5.03 h−1,β=0.458 h−1, K12=2.337 h−1, K21=1.996 h−1 K13=1.154 h−1, Vc=5.508 l, Vp=6.448 l, Vdss=11.956 l. As a function of the pharmacokinetic parameters of cephacetrile, a regimen of multiple doses was established for patients with terminal renal impairment, which will guarantee safe and effective concentrations of the antibiotic.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00644966
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  • 26
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of methadone during maintenance therapy: Pulse labeling with deuterated methadone in the steady state (1979)
    Springer
    European journal of clinical pharmacology 16 (1979), S. 53-57 
    Details
    ISSN: 1432-1041
    Keywords: methadone ; mass fragmentography ; pulse labeling ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A technique is presented for study of steady state kinetics of methadone using pulse labeling with deuterated methadone (d3) and mass fragmentography to measure both unlabeled and labeled methadone in blood. Seven subjects maintained on methadone for at least 10 months were admitted to a closed metabolic ward. The daily dose of unlabeled methadone (d0) was substituted by one dose of methadone-d3 and plasma levels of methadone-d0 and methadone-d3 were followed for 48 h using a precise (SD±5%) and sensitive (30 pmol/ml) mass fragmentographic technique. Plasma half-lives (t1/2) for both methadone-d0 and metadone-d3 were calculated from samples obtained 8–24 h following the dose of methadone-d3. The t1/2 of oral methadone-d3 was shorter (22±2 h) than that of methadone-d0 (52±20 h). The same pattern was observed after intravenous administration. The results indicate multiple pools of methadone in the body.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00644967
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  • 27
    Electronic Resource
    Electronic Resource
    Prazosin, pharmacokinetics and concentration effect (1979)
    Springer
    European journal of clinical pharmacology 16 (1979), S. 177-181 
    Details
    ISSN: 1432-1041
    Keywords: prazosin ; alpha receptor blockade ; blood pressure ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics and effects of prazosin have been studied after intravenous and oral dosing (1 mg) to 6 normal male volunteers. The mean terminal (β) half-life was 2.9 h after intravenous and oral routes. Oral bioavailability was 56.9%. The effects of prazosin on blood pressure were more pronounced after intravenous than oral administration, and the hypotensive effect greater on erect blood pressure. There was a significant correlation (P〈0.02) between the fall in blood pressure and the plasma drug concentration after intravenous prazosin.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00562058
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  • 28
    Electronic Resource
    Electronic Resource
    Influence of the defective metabolism of sparteine on its pharmacokinetics (1979)
    Springer
    European journal of clinical pharmacology 16 (1979), S. 189-194 
    Details
    ISSN: 1432-1041
    Keywords: sparteine ; pharmacogenetic defect ; defective metabolism ; pharmacokinetics ; renal excretion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Sparteine is metabolized by N1-oxidation, which in some subjects is defective. The defect has a pronounced effect on the kinetics of the drug. In non-metabolisers elimination of sparteine proceeds entirely via renal excretion by a capacity-limited process, 99,9% of the dose being excreted as unchanged drug. In metabolisers the drug is mainly eliminated by metabolic degradation. Pronounced differences in β-phase half-life and total plasma clearance were observed between metabolisers (156 min; 535 ml · min−1) and nonmetabolisers (409 min; 180 ml · min−1).
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00562060
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  • 29
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of metformin after intravenous and oral administration to man (1979)
    Springer
    European journal of clinical pharmacology 16 (1979), S. 195-202 
    Details
    ISSN: 1432-1041
    Keywords: metformin ; biguanides ; pharmacokinetics ; absorption
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The kinetics of14C-metformin have been studied in five healthy subjects after oral and intravenous administration. The intravenous dose was distributed to a small central compartment of 9.9±1.61 ( $$\bar X$$ ±SE), from which its elimination could be described using three-compartment open model. The elimination half-life from plasma was 1.7±0.1 h. Urinary excretion data revealed a quantitatively minor terminal elimination phase with a half-life of 8.9±0.7 h. After the intravenous dose, metformin was completely excreted unchanged in urine with a renal clearance of 454±47 ml/min. Metformin was not bound to plasma proteins. The concentration of metformin in saliva was considerably lower than in plasma and declined more slowly. The bioavailability of metformin tablets averaged 50–60%. The rate of absorption was slower than that of elimination, which resulted in a plasma concentration profile of “flip-flop” type for oral metformin.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00562061
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  • 30
    Electronic Resource
    Electronic Resource
    Food-induced reduction in bioavailability of atenolol (1979)
    Springer
    European journal of clinical pharmacology 16 (1979), S. 327-330 
    Details
    ISSN: 1432-1041
    Keywords: atenolol ; food intake ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The influence of food intake on the bioavailability of the beta-adrenoceptor blocker atenolol was assessed by measurement of its single-dose kinetics in ten healthy volunteers, who took 100 mg both in the fasting state and together with a standardized breakfast. Food intake significantly shortened the time to reach peak concentration (2.7 h vs 1.5 h), but caused a significant reduction in AUC values, the mean decrease being 20%. The elimination half-life was unaffected. Atenolol, which is relatively hydrophilic, is incompletely absorbed in the fasting state, and escapes first-pass metabolism. The present findings indicate that food intake causes further impairment of its absorption, even though the absorption rate may initially be enhanced. This contrasts with previous observations on the more lipophilic beta-adrenoceptor blockers propranolol and metoprolol.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00605630
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  • 31
    Electronic Resource
    Electronic Resource
    Multicompartment pharmacokinetics of netilmicin (1979)
    Springer
    European journal of clinical pharmacology 16 (1979), S. 331-334 
    Details
    ISSN: 1432-1041
    Keywords: netilmicin ; radioenzymatic assay ; drug accumulation ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of a single dose of netilmicin (NM) was studied in 6 healthy volunteers. Elimination of the drug was followed in serum and urine for 24 h and 72 h, respectively. NM concentrations were measured with a modified radioenzymatic assay. A three compartment open model was employed to calculate the pharmacokinetic parameters. Following the rapid initial distribution, biphasic elimination with half lives of 1.99 h (t1/2β) and 36.89 h (t1/2γ) was demonstrated. Measurable amounts of NM were excreted in the urine for up to 72 h. The volume of distribution at steady-state (Vdss) of 0.68 l/kg was 3 to 4 times larger than previously reported for this antibiotic. NM plasma clearance was 91 ml/min and the renal clearance was 67 ml/min. The data indicate that on repetitive dosing the amount of drug in the body would be considerably underestimated if the prolonged terminal elimination phase were not taken into account. During prolonged treatment, accumulation of NM in renal and other tissues is likely to occur, as has been described for other aminoglycosides. The possible consequences of this pharmacokinetic behaviour are discussed.
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    URL: http://dx.doi.org/10.1007/BF00605631
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  • 32
    Electronic Resource
    Electronic Resource
    Bioavailability and pharmacokinetics of cimetidine (1979)
    Springer
    European journal of clinical pharmacology 16 (1979), S. 335-340 
    Details
    ISSN: 1432-1041
    Keywords: cimetidine ; enterohepatic circulation ; irregular absorption ; bioavailability ; pharmacokinetics ; volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The bioavailability and pharmacokinetics of cimetidine have been studied in healthy volunteers after administration of single intravenous (100 mg) and oral doses (100, 400 and 800 mg). After i.v. administration, the kinetics of cimetidine could be described by a linear, two compartment open model. Substantial variation in half-life was observed between subjects, with a mean value of 2.1 h (range 0.9–4.7). Cimetidine had a low hepatic extraction ratio and a high total plasma clearance, due to extensive urinary excretion of unchanged drug. After oral administration, the plasma concentration vs time curves in most subjects exhibited two marked peaks, an observation that seemed to be constant within individuals and was independent of dose. Bioavailability, estimated as the area under the plasma concentration vs time curves (AUC), after oral doses as compared to the intravenous dose, in most cases exceeded 100%. There was no correlation between bioavailability estimated as AUC and as urinary excretion of unchanged drug. These observations may indicate an enterohepatic circulatory mechanism, predominantly after oral administration. Both unchanged drug and its sulphoxide metabolite appear to be excreted in bile. The latter was shown in vitro to be reduced to cimetidine by fecal bacteria.
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    URL: http://dx.doi.org/10.1007/BF00605632
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  • 33
    Electronic Resource
    Electronic Resource
    Haemodynamic effects and pharmacokinetics of a new selective beta1-adrenoceptor agonist, prenalterol, and its interaction with metoprolol in man (1979)
    Springer
    European journal of clinical pharmacology 15 (1979), S. 9-13 
    Details
    ISSN: 1432-1041
    Keywords: prenalterol ; metoprolol ; haemodynamics ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The haemodynamic effects of the selectiveβ 1-adrenoceptor agonist prenalterol were studied in healthy subjects before and after therapeutic doses of the selectiveβ 1-adrenoceptor blocker metoprolol. Plasma levels of the drugs were also determined in order to calculate certain pharmacokinetic variables. Intravenous infusion of prenalterol 0.13, 0.25 and 0.50 mg induced a dose-dependent decrease in total electromechanical systole (QA2) and pre-ejection period (PEP). The effect on left ventricular ejection time (LVET) was not significant. Increases in systolic blood pressure and heart rate were dose-dependent. Diastolic blood pressure did not change significantly. When metoprolol had been administered in a cumulative dose of 150 mg (mean maximal plasma level, 284 nmol/1) prenalterol had to be administered in doses that were twelve times higher than before theβ-blocker in order to induce the same haemodynamic effects. Prenalterol was rapidly distributed with an average half life of 8 min. This indicates that distribution equilibrium will be achieved within 30 min after intravenous administration. The overall elimination rate in the post-distributive phase corresponded to an average half life of 2.0 h.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00563552
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  • 34
    Electronic Resource
    Electronic Resource
    Influence of food on the absorption of phenytoin in man (1979)
    Springer
    European journal of clinical pharmacology 15 (1979), S. 269-274 
    Details
    ISSN: 1432-1041
    Keywords: phenytoin ; food-intake ; bioavailability ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The influence of food intake on the absorption of phenytoin was examined in eight healthy volunteers, by study of single-dose kinetics following ingestion of phenytoin 300 mg either with a standardized breakfast or on an empty stomach. Blood samples were collected at regular intervals from 0 to 48 h, and serum concentrations of unmetabolized phenytoin were determined by gas chromatography. Serum concentrations of the major metabolite of phenytoin, 4-hydroxyphenytoin, were measured by mass fragmentography. Concurrent intake of food and phenytoin appeared to accelerate absorption of the drug from the formulation used, and the peak concentrations were significantly higher (mean increase 40%) in the postprandial than in the preprandial state. As reflected by the AUC (area under the curve), the amount of drug absorbed was increased during postprandial conditions, although the difference only reached borderline significance. It is suggested that phenytoin should always be taken in a defined relation to meals.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00618516
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  • 35
    Electronic Resource
    Electronic Resource
    A pharmacokinetic study of neostigmine in man using gas chromatography-mass spectrometry (1979)
    Springer
    European journal of clinical pharmacology 15 (1979), S. 367-371 
    Details
    ISSN: 1432-1041
    Keywords: myasthenia gravis ; neostigmine ; gas chromatography-mass spectrometry ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary To permit rational evaluation of the empirical pharmacotherapy of myasthenia with cholinesterase inhibitors, a sensitive and selective method for the determination of neostigmine has been developed. Analysis is based on ion-pair extraction of neostigmine into methylene chloride and determination by gas chromatography-mass spectrometry (chemical ionization). As neostigmine was found to be metabolized in plasma in vitro, deuterated (d6) neostigmine was immediately added to the plasma sample as the internal standard. The limit of quantitation of the method was about 1 ng/ml (∼ 3nmol/l). The kinetics following i. v. administration were studied in four patients, who received neostigmine 2.5–3.0 mg iv to antagonize pancurone administered during anaesthesia. Elimination was rapid with a half-life t1/2 (β-slope) of 0.89±0.05 h (mean ± SE). The volume of distribution was 1.08±0.11 l/kg and plasma clearance was 0.84±0.04 l/kg/h. In three fasting myasthenic patients plasma concentrations of neostigmine were followed for 5 h after a single oral dose of 30 mg. Considerable interindividual differences in absorption were expressed in the peak concentrations, which occurred 1–2 h following drug ingestion. The bioavailability of neostigmine was estimated to be 1–2% of the ingested dose. Neostigmine concentration in plasma was found to differ considerably (up to forty-fold) between myasthenic patients on their ordinary dose-schedules of cholinesterase inhibitors.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00558442
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  • 36
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of dihydroquinidine in congestive heart failure patients after intravenous quinidine administration (1979)
    Springer
    European journal of clinical pharmacology 16 (1979), S. 101-105 
    Details
    ISSN: 1432-1041
    Keywords: dihydroquinidine ; congestive heart failure ; intravenous administration ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of dihydroquinidine were studied in 8 patients with congestive heart failure following a 22 min intravenous infusion of a quinidine preparation that contained 5.9% dihydroquinidine as an impurity. Using a thin layer chromatography-fluorometric assay procedure for dihydroquinidine, the post-infusion plasma dihydroquinidine concentrations declined biexponentially. The half-life of the fast and slow dispositional processes was 4.42±1.81 min and 6.52±2.40 h, respectively. The central compartment volume for dihydroquinidine in these patients was 0.44±0.11 l/kg with an overall apparent volume of distribution of 1.14±0.38 l/kg. The computed values of total body plasma clearance of dihydroquinidine ranged from 1.29 to 2.69 ml/min/kg with a mean value of 1.94±0.60 ml/min/kg. In these patients, approximately 16% of the administered dihydroquinidine dose was excreted intact into the urine in 48 h. The estimated value of renal clearance was 0.314±0.129 ml/min/kg. When compared to control cardiac patients, the data showed that the apparent volume of distribution for dihydroquinidine is smaller in patients with congestive heart failure and as a result of this diminished volume, the clearance rate of dihydroquinidine was slower. The net effect of these differences was the production of higher plasma concentrations of dihydroquinidine in the heart failure group.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00563115
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  • 37
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of cefoxitin in patients with normal or impaired renal function (1979)
    Springer
    European journal of clinical pharmacology 16 (1979), S. 119-124 
    Details
    ISSN: 1432-1041
    Keywords: cefoxitin ; renal impairment ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of cefoxitin have been determined after a single i.v. injection of 15 mg/kg body weight in 10 patients with normal renal function and 20 patients with varying degrees of renal impairment. The kinetics of the antibiotic followed an open two-compartment model. In patients with normal renal function the following pharmacokinetic parameters were found: $$\begin{gathered} \begin{array}{*{20}c} {\alpha = 8.66 h^{ - 1} } & {\beta = 1.21 h^{ - 1} } & {K_{12} = 3.47 h^{ - 1} } \\ \end{array} \hfill \\ \begin{array}{*{20}c} {K_{21} = 3.17 h^{ - 1} } & {K_{13} = 3.15 h^{ - 1} } & {V_c = 4.24 l.} \\ \end{array} \hfill \\ \begin{array}{*{20}c} {V_p = 4.87 l.} & { Vd_{ss} = 9.11 l.} \\ \end{array} \hfill \\ \end{gathered}$$ In the patients with renal impairment there was a significant decrease in $$\mathop \alpha \limits_, \mathop \beta \limits_, $$ K12, K21 and K13, and an increase in the apparent volume of distribution. The degree of plasma protein binding in patients with normal renal function was 73.6% and this was diminished in patients with renal impairment. A linear relationship between K13 of cefoxitin and creatinine clearance was demonstrated. The dosage regimen for patients with renal impairment should be adjusted by modifying the dosage interval whilst maintaining the amount administered.
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    URL: http://dx.doi.org/10.1007/BF00563118
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  • 38
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of theophylline in young children with asthma: Comparison of rectal enema and suppositories (1979)
    Springer
    European journal of clinical pharmacology 16 (1979), S. 133-139 
    Details
    ISSN: 1432-1041
    Keywords: theophylline ; asthma ; pharmacokinetics ; children
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Six children, aged 2 months – 4 years, received theophylline 5–6 mg/kg intravenously. Its disposition could be described by a two-compartment open model, the mean serum half life (t1/2 β) was 3.75 h, i. e., shorter than in adults, but there was a considerable interindividual variation (1.8–7.0 h, in one patient 13.3 h). Thirteen children (2 months – 4 years) received theophylline suppositories in a dose of 3.8–5.0 mg/kg, and ten (6 months – 4 years) in a dose of 8.4–14.5 mg/kg. Absorption was slow (mean half-time 43 min), incomplete and variable (biological availability 8–100%, mean 80%). Only four of the patients given the higher dose and none given the lower dose reached a therapeutic serum concentration (10–20 µg/ml). Nine children (6 months – 4 years) received rectal enemas of theophylline 4.1–9.2 mg/kg. Absorbtion was rapid (mean half-time 5.5 min) and biological availability averaged 100%. Six patients reached a serum concentration within the therapeutic range. Using the mean values of the calculated pharmacokinetic parameters, rectal enemas providing a dose of theophylline of 6–8 mg/kg t. i. d. were computed to give serum concentrations between 8–20 µg/ml, without producing too high a level during the absorption phase.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00563120
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  • 39
    Electronic Resource
    Electronic Resource
    Kinetics of salicylates in blood and joint fluid (1979)
    Springer
    European journal of clinical pharmacology 16 (1979), S. 279-285 
    Details
    ISSN: 1432-1041
    Keywords: salicylate ; synovitis ; osteoarthritis ; arthritis ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Samples of blood and joint fluid from 30 patients who had taken buffered acetylsalicylic acid were examined for concentrations of total salicylates (TSA), acetylsalicylate (ASA) and salicylate (SA). The data were arranged in groups according to diagnosis of the joint disease. Analysis of the data did not show significant difference in the kinetics of TSA into blood. In groups the time to first appearance of 0.3 mg/l averaged 6.3 min for TSA; these values averaged 7.7 min for ASA and 10.9 min for SA. Close to maximum concentrations in blood averaged 18.9 mg/l for TSA, 3.3 mg/l for ASA, and 23.3 mg/l for SA. The time for first appearance of 0.3 mg/l of total salicylates in joint fluid ranged from 10 to 34 min with an average of 18.1 min; the values of ASA averaged 19.4 min and those of SA 21.9 min. The maximum concentration in joint fluid averaged 15.7 mg/l for TSA, 2.5 mg/l for ASA, and 14.5 mg/l for SA. Transport of salicylates from blood to joint fluid showed a pattern consistent with the type of joint disease. Support was found for the hypothesis that diffusion was the major factor in the movement of salicylates from blood to joint fluid.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00608407
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  • 40
    Electronic Resource
    Electronic Resource
    The disposition of intravenous doxapram in man (1979)
    Springer
    European journal of clinical pharmacology 16 (1979), S. 411-416 
    Details
    ISSN: 1432-1041
    Keywords: doxapram ; intravenous infusion regimen ; pharmacokinetics ; data-point weighting ; healthy subjects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of intravenous doxapram in healthy individuals is consistent with a three-compartment open model. Doxapram was administered by bolus injection (1.5 mg · kg−1) and by intravenous infusion (6.5 mg · kg−1 for 2 h) to 5 subjects on separate occasions. There was no significant difference in mean terminal plasma half-lives (355 and 448 min) or in mean total body clearances (5.9 and 5.6 ml · min−1 · kg−1) following i. v. bolus injection or infusion respectively. In 3 subjects plasma doxapram concentrations during and after i. v. infusion agreed with those predicted from pharmacokinetic values obtained from the bolus injection study. Since mean steady-state concentrations (9.9 µg · ml−1) would be reached only after an extended interval (mean 15.2 h), a variable-rate infusion regimen was calculated to produce and maintain a concentration of 2 µg · ml−1 from 15–25 min onwards. A regimen in which the infusion rate is reduced step-wise is recommended to achieve early near-constant plasma doxapram concentrations.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00568202
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  • 41
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of a single oral dose of muzolimine in cardiac failure (1979)
    Springer
    European journal of clinical pharmacology 15 (1979), S. 105-108 
    Details
    ISSN: 1432-1041
    Keywords: muzolimine ; cardiac failure ; pharmacokinetics ; high ceiling diuretics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of a new “high ceiling” diuretic, muzolimine (Bay g 2821), were investigated after a single oral dose of 40 mg in 7 patients with cardiac failure (Stages I–IV, New York Heart Association classification), and in 2 healthy subjects. Plasma concentrations peaked 1–3 h after administration and declined according to a two-compartment model. The α-phase (distribution phase) lasted until 12–16 h after administration and the mean t1/2α was 3.6 h (range 2.3–4.7) in patients, and 2.6 h (range 2.3–2.9) in healthy subjects. The mean t1/2β was 13.5 h (range 7.4–22.4) in the patients and 14.0 h (range 12.4–14.6) in healthy subjects. T1/2β was not correlated with the degree of heart failure or with the area beneath the plasma concentration curve, which varied three-fold. The renal clearance of muzolimine was in the range 2.7–15.3 ml · min−1 in 5 subjects in whom it was investigated. The pharmacokinetics of muzolimine appear not to be significantly altered by cardiac failure. The prolonged half-lives of the drug are probably responsible for the longer duration of diuretic action reported for muzolimine than for furosemide and bumetamide.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00609872
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  • 42
    Electronic Resource
    Electronic Resource
    Absorption of digoxin in severe right heart failure (1979)
    Springer
    European journal of clinical pharmacology 15 (1979), S. 115-120 
    Details
    ISSN: 1432-1041
    Keywords: digoxin ; right heart failure ; absorption ; absolute bioavailability ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The absorption of digoxin has been investigated in 8 patients before and after successful treatment of severe right heart failure.3H-digoxin 0.1 mg as a solution, and un-labelled digoxin 0.25 mg as a tablet, were given to fasted patients. Blood samples were taken at various time intervals up to 120 hours and urine was collected over the same period. The concentrations of labelled digoxin in plasma and urine were measured in a liquid scintillation counter, unlabelled digoxin was estimated by radioimmunoassay, and various pharmacokinetic parameters were calculated. There was no significant difference in the plasma concentration curves in severe right heart failure and after its successful treatment, nor did any of the calculated pharmacokinetic parameters change significantly. Therefore, inhibition of the absorption of digoxin appears unlikely. In an additional study to estimate absolute bioavailability two different groups of patients in severe right heart failure were given3H-digoxin 0.1 mg or unlabelled digoxin 0.25 mg i. v. and the pharmacokinetic parameters were compared with those from the previous study. The bioavailability of the3H-digoxin solution and of the digoxin tablet were in the same range as values previously published for healthy volunteers, and patients both with and without cardiac failure.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00609874
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  • 43
    Electronic Resource
    Electronic Resource
    Plasma levels and negative chronotropic effect of metoprolol following single doses of a conventional and sustained-release formulation (1979)
    Springer
    European journal of clinical pharmacology 15 (1979), S. 97-103 
    Details
    ISSN: 1432-1041
    Keywords: metoprolol ; tachycardia ; healthy subjects ; conventional tablets ; slow release tablets ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Plasma levels and associated reduction in exercise-induced tachycardia have been examined following the administration of single doses of metoprolol in conventional and slow-release tablets at different times to six healthy male subjects. The study was carried out in two parts. Initially, the tablets were given at 9 a. m. and the subjects were studied up to 14 h and then at 24 h. Subsequently, the same doses were given at 9 p. m. and the subjects were studied 12–24 h after drug administration (i. e. 9 a. m.–9 p. m. the next day). After giving the slow-release tablets the peak plasma levels were significantly lower but the drug persisted in the plasma at higher levels than after the conventional tablet. However, the beta-blocking effect was comparable from the two dosages. The results obtained for the period 12–24 h after the evening dose differed from the corresponding values after morning administration in that the plasma levels were higher and the betablocking effects more marked. Furthermore, the half-life values calculated from these data were significantly longer.
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    URL: http://dx.doi.org/10.1007/BF00609871
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  • 44
    Electronic Resource
    Electronic Resource
    Plasma and urinary levels of triamterene and certain metabolites after oral administration to man (1979)
    Springer
    European journal of clinical pharmacology 16 (1979), S. 39-44 
    Details
    ISSN: 1432-1041
    Keywords: triamterene ; pharmacokinetics ; diuretic effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The plasma and urinary levels of triamterene and two metabolites were measured using a specific method of analysis. Urinary excretion was completed after 48 h, which permitted a rough estimate of its half-life as longer than two hours. The areas under the curve were 672.5±160.3 and 1.311.3±399.1 µg/ml × h after the triameterene 150 mg and 300 mg p.o., respectively and correspondingly 4.2±1.4% and 3.7±0.6% of the dose were excreted as unchanged drug. The principal metabolite of triamterene found was the sulfate conjugate. The area under the curve of this metabolite amounted to 6.672±2.120 and 11.941±5.005 µg/ml × h after the of 150 mg and 300 mg triamterene doses, respectively. The urinary excretion of the metabolite varied between 25.0±4.0% and 17.5±3.5% of the dose after either dose. In healthy subjects an effect on sodium excretion was observed after a dose of 150 mg, whereas the potassium-retaining effect was observed only after the dose of 300 mg.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00644964
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  • 45
    Electronic Resource
    Electronic Resource
    Single- and multiple-dose kinetics of oral lorazepam in humans: The predictability of accumulation (1979)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 7 (1979), S. 159-179 
    Details
    ISSN: 1573-8744
    Keywords: lorazepam ; benzodiazepines ; pharmacokinetics ; drug accumulation ; antipyrine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Six healthy volunteers participated in single- and multiple-dose pharmacokinetic studies of oral lorazepam. Following single 4-mg oral doses, peak plasma lorazepam concentrations ranging from 40 to 70 ng/ml were reached within 3 hr of the dose. Values of absorption half-life averaged 25min (range 10.3–42.7min), and elimination half-life (t 1/2β ) averaged 14.2 hr (range 8.4–23.9 hr). During 15 consecutive days of 3 mg per day administered in divided doses, accumulation to the steady-state condition was complete within several days of the initiation of therapy. Values of accumulation half-life (mean 21.1 hr) were slightly longer than t 1/2β , and the two were not well correlated. Observed accumulation ratios (mean 1.88) were very close to those predicted from the single-dose study (mean 1.77), but the correlation between the two (r=0.51) was not significant in the small sample size. “Washout” half-life values (mean 14.9 hr) were highly correlated with t 1/2β (r=0.92). Clearance of a single intravenous dose of antipyrine determined prior to the multiple- dose lorazepam study (mean 0.86 ml/min/kg) was essentially identical to that determined after the study (mean 0.87 ml/min/kg). Overall, the rate and extent of lorazepam accumulation during multiple dosage were reasonably well predicted by the single-dose kinetic study. However, accurate prediction for any specific individual was not always achieved. Stimulation or inhibition by lorazepam of its own clearance probably does not explain imprecise prediction, since single-dose t 1/2β .
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01059736
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  • 46
    Electronic Resource
    Electronic Resource
    Clinical pharmacokinetics of procainamide infusions in relation to acetylator phenotype (1979)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 7 (1979), S. 69-85 
    Details
    ISSN: 1573-8744
    Keywords: procainamide ; pharmacokinetics ; constant-rate infusion ; acetylator phenotype ; pharmacogenetics ; renal impairment
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The pharmacokinetics of procainamide was determined in 21 lidocaine-resistant patients who received the drug according to a pharmacokinetically designed double-infusion technique. Thirteen patients were phenotyped as slow acetylators, seven as fast, and one as intermediate. The total body clearances (ClT) of PA in slow and fast acetylators were 22.6 and 34.8 liters/hr, respectively. The fraction of PA cleared by the formation of NAPA in the corresponding acetylator group was 0.2 and 0.4. Renal impairment affected the pharmacokinetics of PA more profoundly as the ClTs of PA in patients with and without renal impairment were 17.9 and 31.2 liters/hr, respectively. None of the calculated volumes of distribution was affected by acetylator phenotype or renal impairment. These data identify the contribution of at least two of the major factors accounting for variability in PA disposition in patients undergoing therapy.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01059442
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  • 47
    Electronic Resource
    Electronic Resource
    Disposition of synthetic glucocorticoids I. Pharmacokinetics of dexamethasone in healthy adults (1979)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 7 (1979), S. 249-264 
    Details
    ISSN: 1573-8744
    Keywords: dexamethasone ; pharmacokinetics ; renal excretion ; high-performance liquid chromatography
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The pharmacokinetics of dexamethasone alcohol is described in six male and six female healthy adult volunteers who each received 8 mg of dexamethasone phosphate by bolus intravenous injection. Quantitation of the alcohol was done using a high-performance liquid Chromatographic method with improved specificity. Statistical evaluation of the results generated by nonlinear least-squares regression analysis of the plasma concentration-time data shows that the phosphate ester is very rapidly hydrolyzed to the alcohol and a biexponential equation is the simplest poly exponential equation that is consistent with the data. The terminal phase half-lifet 1/2β was significantly greater (p〈0.05) in males (mean 201.5 min) than in females (mean 142.3 min). The prolongedt 1/2β in males did not appear to be caused by an impaired capacity to eliminate dexamethasone since the total plasma clearance did not differ between males (mean 247.5ml/min) and females (mean 242.9 ml/min). There was, however, a high positive correlation betweent 1/2β and $$V_{d_{ss} } $$ among the 12 adults (r=0.92, p〈0.001). There were also significant correlations between $$V_{d_{ss} } $$ and body weight (r=0.67, p〈0.05) andt 1/2β (r=0.80, p〈0.01).The difference in body weight between the sexes seems to be the main factor contributing to the difference observed in t 1/2β. An average of only 2.6% of the dose was found unchanged in a 24-hr urine sample, and hence it appears that dexamethasone is primarily eliminated by extrarenal, probably hepatic, mechanisms.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01060016
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  • 48
    Electronic Resource
    Electronic Resource
    Chlorpheniramine. II. Effect of the first-pass metabolism on the oral bioavailability in dogs (1979)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 7 (1979), S. 383-396 
    Details
    ISSN: 1573-8744
    Keywords: chlorpheniramine ; pharmacokinetics ; oral absorption ; first-pass effect ; saturation kinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The pharmacokinetics of chlorpheniramine has been studied in six dogs by following the time course of plasma concentration of the drug after intravenous and oral administration of its maleate salt in solution form. After intravenous dosing the decline in chlorpheniramine plasma concentration was typically biexponential. The drug distributed rapidly and extensively to the extravascular tissues. The mean distribution phase halflife was 12.5 min, and the mean apparent volume of distribution, Vdβ, was 525% ofthe body weight in four dogs with normal hematocrits. The mean half-life of elimination was 1.7hr. The percent absolute availability following oral administration of the drug in the aqueous solution form was found to be dose dependent. At 100-mg dose, in six dogs, an average of 36% of the orally administered dose was found to be systemically available. At 50-mg dose, in one of the four dogs studied, no measurable plasma levels of chlorpheniramine were obtained, and the average bioavailability was only 9.4%. The average availability in four dogs at 200-mg dose was 39.4%. Even at 200-mg oral dose, the dogs did not show any signs of sedation and remained alert all through the experiment. Saturable first-pass gut and/or hepatic elimination has been postulated. The possible implications of these findings on the therapeutic effectiveness of the usual dosing regimen of chlorpheniramine in dogs are discussed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01062536
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  • 49
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of clonidine in the rat and cat (1979)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 7 (1979), S. 481-494 
    Details
    ISSN: 1573-8744
    Keywords: clonidine ; pharmacokinetics ; blood and brain levels ; liver clearance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract To investigate the pharmacokinetic behavior of clonidine, rats were given clonidine intravenously at 125, 250, and 500μg/kg and blood clonidine concentrations were followed for 6 hr. The disposition of clonidine in two brain regions was studied in rats after an i. v. dose of 500 μg/kg. The liver clearance in rats was investigated by liver perfusion techniques. The results obtained indicate that the disposition characteristics of clonidine can be described by a two-compartment open model in both rats and cats. The penetration of clonidine into tissues is rapid, and brain levels in rats were about 1.7 times higher than blood levels. Brain tissues were found to be an indistinguisible part of the central (blood) compartment. Dose-dependent pharmacokinetic behavior was found for clonidine in rats at the doses used. This was demonstrated by a decrease of both the rate constant of distribution to the peripheral compartment and the overall elimination rate constant from the body, with increase in dose. As a consequence, the volume of distribution and the clearance both decreased with increasing dose. Possible explanations for the dose-dependent behavior of clonidine are discussed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01062390
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  • 50
    Electronic Resource
    Electronic Resource
    Potential pitfalls in the conventional pharmacokinetic studies: Effects of the initial mixing of drug in blood and the pulmonary first-pass elimination (1979)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 7 (1979), S. 527-536 
    Details
    ISSN: 1573-8744
    Keywords: instantaneous distribution ; pharmacokinetics ; pulmonary first-pass effect
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The classical concept of assuming that an i.v. dose instantaneously distributes into the central or plasma compartment is reviewed, as is the potential for pulmonary first-pass effect. Based on available literature, the concept is shown to lead to serious errors in estimating pharmacokinetic parameters, particularly for drugs with high clearance.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01062393
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  • 51
    Electronic Resource
    Electronic Resource
    Multiple receptor responses: A new concept to describe the relationship between pharmacological effects and pharmacokinetics of a drug: Studies on clonidine in the rat and cat (1979)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 7 (1979), S. 495-510 
    Details
    ISSN: 1573-8744
    Keywords: clonidine ; pharmacokinetics ; analgesia ; blood pressure effects ; smooth muscle
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The time course of an observed pharmacological effect is affected not only by the kinetics of the drug levels at the site of action but also by parameters such as the slope and maximum effect of the functional relationship between drug level and response. Using clonidine as a test drug, it was found that the kinetics of its effects on blood pressure and pain responses cannot be described by the time course of clonidine levels in the blood, brain, or the hypothetical tissue compartment of the two-compartment characteristics of this drug. However, the results can be explained assuming that the observed pharmacological effects of a drug are composed of the sum of responses from at least two receptor sites with different slopes and maximal effects. The effect of intravenously administered clonidine on blood pressure in the rat was found to be related to the blood concentrations at least at two receptor sites with opposite effects, one leading to a hypertensive and the other to a hypotensive response. Predictions indicate that a maximum decrease of arterial blood pressure is obtained when the steady-state blood concentration of clonidine is about 1 ng/ml and that no effect is seen at 10 ng/ml. Higher levels will produce an increase of the pressure. The kinetics of the analgesic effect of clonidine in the rat could best be related to the brain levels if the observed effect was considered to be derived from the sum of activity at two receptor sites each producing analgesia. The kinetics of the effects of clonidine on the nictitating membrane of the cat was found to be determined by the kinetics of the drug in the peripheral compartment of the two-compartment open model. Consideration of multiple receptor responses is suggested for future studies on the relationship between the kinetics of drug levels and pharmacological responses.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01062391
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  • 52
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of digoxin: Relationship between response intensity and predicted compartmental drug levels in man (1979)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 7 (1979), S. 47-61 
    Details
    ISSN: 1573-8744
    Keywords: digoxin ; pharmacokinetics ; response kinetics ; three-compartment model ; serum digoxin kinetics ; systolic time intervals ; radioimmunoassay
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract A study designed to investigate the relationship between the pharmacokinetics of digoxin and a measure of its pharmacological effect has been conducted. Serum digoxin concentrations and systolic time intervals were measured concurrently in 12 normal male volunteers following a 1.0 mg i.v. bolus injection. The averaged serum digoxin concentration- time and response-time data were analyzed pharmacokinetically using a three-compartment open model and nonlinear least- squares fitting. When only the serum level-time data were analyzed, a close relationship was found between calculated digoxin levels in the slowly distributing (deep) peripheral compartment and response of the heart to digoxin, as measured by changes in the QS2 index δQS2I. Although it was not possible to distinguish clearly a linear from a nonlinear relationship between digoxin levels in the deep compartment and δQS2I, the nonlinear relationship gave the best overall fit when both serum digoxin and δQS2I data were fitted simultaneously. The simultaneous fityielded a total body clearance of digoxin of 3.6 ml/min/kg and a terminal t1/2 of 42 hr.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01059440
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  • 53
    Electronic Resource
    Electronic Resource
    Kinetics of biotransformation of clonazepam to its 7-amino metabolite in the monkey (1979)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 7 (1979), S. 87-95 
    Details
    ISSN: 1573-8744
    Keywords: clonazepam ; in vivo biotransformation ; 7-amino metabolite ; pharmacokinetics ; monkeys ; anticonvulsants
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The pharmacokinetic behavior of the 7-amino metabolite of clonazepam administered exogenously and formed endogenously from the parent drug was studied in a group of rhesus monkeys using constant rate intravenous infusions. Plasma levels of the 7-amino metabolite and/or clonazepam were determined with a GC-CI-MS method. The biological half-life of the 7-amino metabolite (2.2 ± 1.0 hr) was shorter than that of clonazepam (4.9 ± 0.2 hr). Total body clearance of the metabolite (0.83 ± 0.16 liters/hr/kg) was larger than that of the parent drug (0.55 ± 0.09 liters/hr/kg). The kinetics of in vivo biotransformation were described by a two- compartment model in which formation and disposition of the metabolite follow first-order processes. The fraction of a dose of clonazepam appearing in the systemic circulation as 7-amino metabolite was 0.70 ± 0.30. This value may underestimate the actual fraction formed, if the metabolite is susceptible to first- pass metabolism following in situ formation.
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    URL: http://dx.doi.org/10.1007/BF01059443
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  • 54
    Electronic Resource
    Electronic Resource
    Attenuation of furosemide's diuretic effect by indomethacin: Pharmacokinetic evaluation (1979)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 7 (1979), S. 265-274 
    Details
    ISSN: 1573-8744
    Keywords: furosemide ; indomethacin ; prostaglandin ; pharmacokinetics ; pharma-codynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The pharmacokinetics and pharmacodynamics of intravenous furosemide, 40 mg, were studied in four normal males in a crossover fashion with and without indomethacin pretreatment. In each study 16 plasma and 10 urine samples were collected over 24 hr. Fluid and electrolyte urinary losses were replaced orally throughout the study. Unchanged furosemide and indomethacin were measured using HPLC; urinary sodium was measured by flame photometry. Pretreatment with indomethacin resulted in increased and prolonged furosemide plasma levels, increased area under the curve, decreased plasma clearance, decreased renal clearance, increased half-life, no change in volume of distribution, and decreased sodium excretion and urine volume. Analysis of sodium excretion rate with time shows that the inhibiting effect of indomethacin was greater during the first 2 hr than at later times.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01060017
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    Pharmacokinetics of phenylethylacetylurea (pheneturide), an old antiepileptic drug (1979)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 7 (1979), S. 453-462 
    Details
    ISSN: 1573-8744
    Keywords: pheneturide ; antiepileptics ; pharmacokinetics ; TLC-UV densitometry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The pharmacokinetics of pheneturide (a decarboxylation product of phenobarbital), used to prevent psychomotor seizures for many years, was studied in normal human volunteers. To measure the drug in plasma and urine, a highly sensitive and reproducible thin-layer chromatography-reflectance spectrophotometric assay was developed. The results show that pheneturide follows first-order kinetics in the dose range studied. Its half-life after single doses is 54 hr (range 31–90), and its total body clearance (100% nonrenal) is 2.6 liters/hr (range 1.73–3.59). After repetitive administration, half-life is 40 hr (but clearance remains unchanged because of a lower volume of distribution). Because of the long half-life, repetitive administration results in a continuous steady-state level and makes this drug (kinetically) ideal for long-term use.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01062387
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  • 56
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    Electronic Resource
    Plasma levels and β-blocking effect of α-hydroxymetoprolol—Metabolite of metoprolol—in the dog (1979)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 7 (1979), S. 471-479 
    Details
    ISSN: 1573-8744
    Keywords: metoprolol ; α-OH-metoprolol ; active metabolites ; pharmacokinetics ; β- blocking effect
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The plasma levels and the β- blocking effect of metoprolol and its active metabolite α- hydroxymetoprolol have been studied after i.v. bolus injections of the substances to dogs. For both substances the β- blockade increased with the dose, and there was a linear relationship between percent reduction in exercise heart rate and the logarithm of plasma concentration. The dose of the metabolite, however, had to be 5 times higher than that of metoprolol to induce the same degree of β- blockade. Because of differences in the volume of distribution, 2.0 liters/kg for α- OH-metoprolol and 3.5 liters/kg for metoprolol, the 5 times higher dose of α- OH-metoprolol resulted in 10 times higher plasma levels of the metabolite than of metoprolol. α- OH-Metoprolol was more slowly eliminated (t1/2∼7.0 hr, total body clearance ∼3.5 ml-kg−1-min−1) than metoprolol (t1/2∼2.0 hr, total body clearance ∼20.0 ml-kg−1-min−1). Approximately 5% of an i.v. dose of metoprolol was metabolized to α- OH-metoprolol. The half-life of the endogenously formed metabolite was the same as after an i.v. dose of the compound.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01062389
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  • 57
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    Plasma level of chlormethiazole and two metabolites after oral administration to young and aged human subjects (1977)
    Springer
    European journal of clinical pharmacology 12 (1977), S. 137-145 
    Details
    ISSN: 1432-1041
    Keywords: Chlormethiazole ; pharmacokinetics ; metabolites ; oral administration ; young and elderly human subjects ; quantitative gas chromatographymass spectrometry ; whole blood distribution
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The plasma concentration of chlormethiazole and two of its metabolites has been measured in three young and three aged human subjects following administration of a single oral dose of chlormethiazole. A sensitive analytical method based on gas chromatography-mass spectrometry using the selective ion monitoring mode of operation was developed to permit quantitation of the plasma levels. The time course of the plasma concentration of chlormethiazole and metabolites showed wide inter-subject variation, particularly between the young and elderly subjects. Absorption of chlormethiazole was rapid in the subjects of both groups as assessed by the time taken to reach the peak plasma concentration. The mean peak plasma level of chlormethiazole was more than five times greater in the elderly (2.90±1.56 µg/ml) than in the young (0.55±0.58 µg/ml) subjects. The plasma level of chlormethiazole was consistently higher in the aged subjects and this was reflected by the larger area under the plasma curve in aged (7.62±5.37 µg.h/ml) than in young (0.94±0.66 µg.h/ml) individuals. Decreased pre-systemic elimination by the liver has been suggested as an important factor contributing to the higher plasma level in the elderly. Estimates of absolute systemic availability, calculated by reference to previous intravenous studies, were greater for the elderly subjects. The distribution of chlormethiazole in whole blood from six young and six elderly human subjects was investigated in vitro. The unbound fraction of chlormethiazole in plasma increased significantly from 0.308±0.035 in young subjects to 0.403±0.067 in the elderly. Distribution of the drug in whole blood was different for the two age groups; the fraction of drug distributed to plasma water was significantly greater and the fraction in blood cells was significantly less in the aged.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00645135
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  • 58
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    Electronic Resource
    Pharmacokinetics of tolamolol in the treatment of hypertension (1977)
    Springer
    European journal of clinical pharmacology 12 (1977), S. 171-174 
    Details
    ISSN: 1432-1041
    Keywords: Tolamolol ; hypertension ; pharmacokinetics ; mean steady-state concentration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Tolamolol was administered in a “double-blind” study to fifteen hypertensive patients by dose-titration against arterial blood pressure. Mean steady-state plasma tolamolol concentrations (Css) were determined for each patient from the area under the plasma concentration — time curve during a dosage interval whilst patients were receiving optimal tolamolol doses. No significant correlation was observed between daily tolamolol dose and Css; the relationship between fall in lying mean arterial pressure and Css also failed to reach conventional levels of statistical significance, but Css was observed to be correlated with the fall in standing pressure. The results suggest that plasma concentrations in excess of 200 ng/ml may be required to achieve an effective hypotensive response with the drug.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00609855
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  • 59
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    Electronic Resource
    Comparison of the pharmacodynamic effects of furosemide and BAY g 2821 and correlation of the pharmacodynamics and pharmacokinetics of BAY g 2821 (muzolimine) (1977)
    Springer
    European journal of clinical pharmacology 12 (1977), S. 341-344 
    Details
    ISSN: 1432-1041
    Keywords: Muzolimine ; pharmacodynamics ; pharmacokinetics ; furosemide ; saluresis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In a biometrically planned, double-blind study on 12 Oedema-free male patients the saluretic effect of muzolimine 30 mg was compared with furosemide 40 mg. The plasma level of muzolimine was determined and correlated with its pharmacodynamics. In terms of excretion during the 12-hour observation period muzolimine 30 mg had as great a cumulative effect as furosemide 40 mg. There was a significant difference in the time-response curve. During the first two hours furosemide 40 mg had more saluretic effect than muzolimine 30 mg. Between two and four hours there was no significant difference between the two substances. Between four and six hours, however, muzolimine was somewhat more effective than furosemide, although the difference did not reach the level of significance. After 6 h there was no longer any difference between the two compounds. The half-life of the fall in concentration of muzolimine in plasma was 3.7 up to 10 h after its administration. The time-response curve of the increased urine excretion correlated well with the time course of the concentration of muzolimine in plasma.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00562448
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  • 60
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    Electronic Resource
    Disposition of valproic acid in man (1977)
    Springer
    European journal of clinical pharmacology 12 (1977), S. 125-132 
    Details
    ISSN: 1432-1041
    Keywords: Valproic acid ; pharmacokinetics ; saliva concentration ; urinary excretion ; serum protein binding
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of valproic acid (VPA) have been studied in 6 healthy subjects following a single 600 mg dose, and after multiple doses over 12 days (1200 mg daily) of enteric-coated sodium valproate. A time lag before absorption of 1 to 2 h was observed in each subject, and then absorption was rapid, peak concentrations being recorded 3 to 4 h after administration of the dose. The plasma level decline was biphasic with a terminal half-life of 15.9±2.6 h in the single dose and 17.3±3.0 h in the multiple dose experiments. There was no evidence of dose dependent kinetics or autoinduction. Total plasma clearance was 0.0064±0.0011 l/kg×h. The apparent volume of distribution was small at 0.15±0.2 l/kg. The mean steady state plasma concentration (Css) reached after 4 days was 81.3±13.0 µg/ml. Css observed was lower than Css predicted (99.2±14.7 µg/ml) from single dose kinetics (p〈0.001). The difference was probably due to a reduction in plasma protein binding at higher concentrations. VPA concentration in saliva was between 0.4 and 4.5% of the total plasma concentration and was not equal to the concentration of unbound drug in plasma (6.7±0.8% unbound). 3.2% of the dose was excreted in urine as the parent drug and 21.2% as conjugated metabolites.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00645133
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  • 61
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    Effect of exercise on the serum level and urinary excretion of tetracycline, doxycycline and sulphamethizole (1977)
    Springer
    European journal of clinical pharmacology 12 (1977), S. 367-373 
    Details
    ISSN: 1432-1041
    Keywords: Sulphamethizole ; tetracycline ; doxycycline ; rest ; exercise ; pharmacokinetics ; excretion ; absorption
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The serum level and urinary excretion of sulphamethizole, tetracycline and doxycycline were studied in healthy volunteers subjected to intensive exercise and bed rest in a cross-over trial. Each group consisted of 7–8 subjects. The exercise or bed rest began 15 min before oral administration of the drug and was continued for the following 4 hours. During exercise serum drug concentration and the area under the serum concentration-time curve for each agent was significantly higher (p〈0.05) than the corresponding values at rest. Exercise greatly suppressed the renal excretion of tetracycline and doxycycline, but the decrease alone appeared insufficient to account for the pronounced increase in serum drug concentration. Total drug excretion in urine was unchanged. Thus, it seemed most unlikely that overall absorption from the gastrointestinal tract had been altered by exercise. However, the rate of absorption appeared to be more rapid in the exercise than in the rest period. Marked haemoconcentration was not produced by the exercise. In addition to changes in absorption and elimination rates, alteration in the volume of distribution might contribute to the higher serum drug concentration during exercise. Therefore, the level of physical activity should be considered in the interpretation of pharmacokinetic data both in clinical practice and in pharmacokinetic studies.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00562453
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  • 62
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    Fluorometric determination of hydroflumethiazide in human plasma and urine after its oral administration (1977)
    Springer
    European journal of clinical pharmacology 11 (1977), S. 149-154 
    Details
    ISSN: 1432-1041
    Keywords: Hydroflumethiazide ; spectrofluorometry ; pharmacokinetics ; plasma half life ; renal excretion ; renal disease
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A spectrofluorometric method for determination of hydroflumethiazide in human plasma and urine has been developed. The limit of detection was 10 ng/ml plasma and 100 ng/ml urine. The plasma concentration of hydroflumethiazide was determined for 9–11 hours and excretion in urine for 24–37 hrs after oral administration of about 1 mg/kg body weight to 7 subjects. Plasma half life in healthy subjects was 1.9–2.1 h, and 2.7–8.6 h in patients during the period 4–9 hrs after dosing. Cumulative excretion in urine was 67–79% of the dose during 31–37 hrs in 6 subjects; one patient with renal disease was found to excrete only 25.8% of dose during 24 hours. Renal clearance of hydroflumethiazide was higher in the healthy subjects (0.29–0.44 1 h−1 kg−1) than in the patients (0.040–0.15 l h−1 kg−1). Plasma half life of hydroflumethiazide was not closely correlated with renal clearance of the drug, which suggests that other factors may play a role in determining plasma half life.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00562907
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  • 63
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    Transfer of nitrazepam across the human placenta (1977)
    Springer
    European journal of clinical pharmacology 12 (1977), S. 355-357 
    Details
    ISSN: 1432-1041
    Keywords: Nitrazepam ; placental transfer ; pharmacokinetics ; plasma levels ; protein binding
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Six women from 14 to 17 weeks pregnant, and 12 woman from 36 to 40 weeks pregnant, were given nitrazepam 5 mg orally about 12 h before legal abortion by hysterotomy in the former group and elective caesarean section in the latter group. The concentration of nitrazepam was determined by gas-liquid chromatography. Binding to plasma proteins was evaluated by separation of the protein-free fraction by ultracentrifugation. In the first group (early pregnancy) the level of nitrazepam was found to be lower in the fetal than in the maternal circulation. The concentration in amniotic fluid was still lower. In the latter group (late pregnancy) the concentration both of unbound and total nitrazepam in maternal and fetal plasma were in equilibrium, which indicated an increase in transplacental transfer in late pregnancy. The percentage of unbound nitrazepam in both cases was 12%.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00562451
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  • 64
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    Human pharmacokinetics and bioavailability of temazepam administered in soft gelatin capsules (1977)
    Springer
    European journal of clinical pharmacology 12 (1977), S. 383-386 
    Details
    ISSN: 1432-1041
    Keywords: Benzodiazepine ; temazepam ; pharmacokinetics ; bioavailability ; hard and soft gelatine capsules
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Plasma levels of temazepam were determined in healthy subjects after single oral administration of soft and hard gelatin capsules, and after 7 consecutive night-time doses in soft capsules. Absorption from soft gelatin capsules was significantly faster and produced earlier and higher peak plasma levels. The two pharmaceutical forms did not show any significant difference in relative availability. The apparent half-life of temazepam after night-time administration was significantly shorter than after morning administration, but no change in half-life was observed between the first and seventh night-time doses.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00562455
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  • 65
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    Overall pharmacokinetics during prolonged treatment of healthy volunteers with digoxin andβ-methyldigoxin (1977)
    Springer
    European journal of clinical pharmacology 12 (1977), S. 387-392 
    Details
    ISSN: 1432-1041
    Keywords: Digoxin ; β-methyldigoxin ; prolonged administration ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Five healthy volunteers received digoxin 0.4 mg or β-methyldigoxin 0.4 mg i. v., daily for 14 days, in a randomized cross-over arrangement. By monitoring minimal plasma concentrations during multiple dosing, it was found that the steady state pharmacokinetics of digoxin and β-methyldigoxin could be estimated even better by a one-compartment than by a two-compartment model. The following mean parameters were calculated: the half life of digoxin of 1.54±0.31 days was significantly shorter than the half life of 2.29±0.34 days for β-methyldigoxin. The distribution volume of 807±187 liters for digoxin was not significantly larger than the 735±227 liters for β-methyldigoxin. Renal digoxin clearance of 191±25 ml/min was significantly higher than both the renal clearance of β-methyldigoxin of 111±23 ml/min and also the creatinine clearance, which indicates tubular secretion of digoxin. There was a 2.8-fold accumulation of β-methyldigoxin injected once a day, which was significantly higher than the 1.8-fold accumulation of digoxin.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00562456
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  • 66
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    The pharmacokinetics of carbamazepine (1977)
    Springer
    European journal of clinical pharmacology 12 (1977), S. 451-456 
    Details
    ISSN: 1432-1041
    Keywords: Bioavailability ; carbamazepine ; elimination ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The time-courses of plasma carbamazepine concentrations were followed in six apparently healthy adult subjects who, at different times, took single oral drug doses of 200, 400, 500, 600, 700, 800 and 900 mg. There were some suggestions of impaired bioavailability of the drug when given in tablet form. The following values were obtained for various pharmacokinetic parameters:k abs =0.176±0.209 h−1;k=0.0203±0.0055 h−1; T1/2=37.5±13.1 h; VD=0.825±0.1041 · kg−1; Clearance=0.0163±0.0061 l · kg−1. The elimination rate constant showed a statistically significant increase with increasing drug dose. This may help explain the clinical observation that the rate of rise of steady state plasma carbamazepine concentrations tends to decrease with dose increase in patients taking carbamazepine alone.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00561065
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  • 67
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    Behaviour of glibenclamide on repeated administration to diabetic patients (1977)
    Springer
    European journal of clinical pharmacology 11 (1977), S. 19-25 
    Details
    ISSN: 1432-1041
    Keywords: Diabetes mellitus ; sulfonylurea ; glibenclamide ; pharmacokinetics ; repeated administration ; deep compartment
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Six maturity onset diabetic patients took glibenclamide 5 mg by mouth, every morning 10 min before a standard breakfast. Serum levels of immunoreactive glibenclamide, glucose and immunoreactive insulin were measured repeatedly on the first and 15th days of treatment. Measured glibenclamide blood levels were in close agreement with an analogue computer simulation of data obtained from healthy volunteers: there was no accumulation of drug in the blood, but there was strong evidence for the existence of a slowly equilibrating “deep” compartment. Considerable insulin release and correction of the breakfast-induced hyperglycaemia were observed immediately after administration of the drug, as well as 5 h later, at lunch time. The clinical significance of blood levels of glibenclamide, as well as the correlation of pharmacokinetics with pharmacodynamics, are discussed in the light of these results.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00561783
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  • 68
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    Electronic Resource
    Model independent derivation of general equations for the “first-pass” effect and extra-hepatic drug elimination (1977)
    Springer
    European journal of clinical pharmacology 11 (1977), S. 57-64 
    Details
    ISSN: 1432-1041
    Keywords: General equation ; pharmacokinetics ; first pass effect ; extra-hepatic drug elimination
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A general expression for the ratio of areas below the blood concentration-time curves after intravenous and oral drug administration is derived. This derivation does not require the assumption of a specific compartmental model to describe drug distribution within the body. Similarly an expression for the amount of drug metabolised in the liver is derived. The latter expression is used to estimate the extent of extra-hepatic drug elimination from the body.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00561789
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  • 69
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    Pharmacokinetic aspects of protriptyline plasma levels (1977)
    Springer
    European journal of clinical pharmacology 11 (1977), S. 51-56 
    Details
    ISSN: 1432-1041
    Keywords: Antidepressive agent ; protriptyline ; plasma concentration ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Plasma levels of protriptyline have been determined in 30 depressed female patients undergoing antidepressant therapy. After 3 1/2 weeks treatment at dosage levels of 40 mg/day, protriptyline plasma levels ranged from 430 to 1430 nmol/l. During this period only two-thirds of the subjects had definitely achieved asymptotic concentrations. Single dose studies in 5 volunteers suggest that the volume of distribution of protriptyline shows little intersubject variation. The half life of the drug, however, may vary appreciably from subject to subject, ranging from 54 to 198 h. The effects of two sedatives on mean protriptyline plasma levels have been determined. Mean plasma levels for nitrazepam recipients are indistinguishable from those for patients receiving no night sedation. The mean plasma levels for a group of patients receiving sodium amylobarbitone were significantly reduced. The problem of choice and early adjustment of dosages in order to achieve satisfactory plasma levels is discussed. For practical purposes it is suggested that early values may be of predictive significance in allowing early dosage adjustments to be made.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00561788
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  • 70
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    Pharmacokinetics of salicylate and indomethacin in coeliac disease (1977)
    Springer
    European journal of clinical pharmacology 11 (1977), S. 473-477 
    Details
    ISSN: 1432-1041
    Keywords: Salicylate ; aspirin ; indomethacin ; pharmacokinetics ; coeliac disease
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The plasma concentrations of salicylate and indomethacin were measured after a single oral dose of aspirin (600 mg) and indomethacin (50 mg) in twelve starved normal subjects and twelve adult patients with coeliac disease. The absorption of salicylate in the coeliac patients was faster than in the normal subjects. The plasma concentration/time curve of indomethacin in both groups was similar during the absorption phase, but there were significant differences between the groups in its elimination. The abnormal absorption pattern of salicylate in coeliac disease does not appear to be related to its pKa. Possible causes of the difference in salicylate absorption include changes in gastric emptying or altered small intestinal permeability.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00562942
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  • 71
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    Human experience of cetiedil, a new vasodilator with anticholinergic properties (1977)
    Springer
    European journal of clinical pharmacology 12 (1977), S. 205-208 
    Details
    ISSN: 1432-1041
    Keywords: Cetiedil ; vasodilator ; anticholinergic drug ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Cetiedil, a new vasodilating drug with anticholinergic properties, was shown to be metabolised very rapidly in man after intravenous and oral administration of the14C-compound. Higher concentrations of labelled compound after oral than after intravenous administration at the same sampling time, and proportional differences in urinary excretion, suggest that metabolic handling of the drug differs depending on the route of administration. Experiments in which inhibition of saliva secretion was measured indicated that (an) active metabolite(s) probably was (were) responsible for the action of the drug. As an anticholinergic drug, cetiedil is at least 400 times weaker than atropine.
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    URL: http://dx.doi.org/10.1007/BF00609862
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  • 72
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    The pharmacokinetics of cefuroxime after intravenous injection (1977)
    Springer
    European journal of clinical pharmacology 12 (1977), S. 221-227 
    Details
    ISSN: 1432-1041
    Keywords: Cefuroxime ; cephalosporin antibiotics ; intravenous injection ; pharmacokinetics ; volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Cefuroxime, a new cephalosporin antibiotic which is stable to most β-lactamases produced by Gram-negative bacteria, was given by bolus intravenous injection to six volunteers in doses of 500 mg and 750 mg. The concentrations of cefuroxime in serum and urine were measured at pre-determined times after injection and the data analysed by a two-compartment open system model. A serum concentration of 8 µg/ml was exceeded for 100.3 min (±18.3) after a 500 mg dose and for 144.5 min (±19.8) after 750 mg. The ultimate serum half-life was 1.1 h. Excretion of cefuroxime in the urine was almost complete in 24 h, the clearance being 150 ml/min/1.73 m2. About 45% was excreted through the renal tubules. The injections were well tolerated and no changes in haematological or biochemical values were seen. The resulting data are compared with those published for some other cephalosporins. It is concluded that the favourable pharmacokinetics, especially the high concentrations of unbound cefuroxime in the serum, are likely to aid effective therapy of human infection caused by sensitive bacteria.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00609865
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  • 73
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    Electronic Resource
    Antiarrhythmic and electrocardiographic effects of single oral doses of disopyramide (1977)
    Springer
    European journal of clinical pharmacology 11 (1977), S. 91-99 
    Details
    ISSN: 1432-1041
    Keywords: Disopyramide ; plasma concentration ; cardiodepressant drugs ; ventricular arrhythmia ; ventricular tachycardia ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Ten patients with various heart diseases and ventricular arrhythmia received a single oral dose of disopyramide (DE) 200 mg. The ECG was recorded continuously for about 50 h from 2–4 h before drug administration. A statistically significant reduction in the number of ventricular ectopic beats (VEBs) was seen 1.0–3.5 h after drug intake; the average number of VEBs per 30 min decreased from 317 during the control period to 92 by 1.0–3.5 h after treatment and if one patient who did not respond is excluded, the corresponding figures were 272 and 14, respectively. Consecutive VEBs were seen in seven patients before DE was given and decreased significantly (p〈0.05) 1.5–5.5 h after drug administration. There was no change in the PQ interval, the QRS interval showed a slight increase, whereas the QT interval was prolonged 0.5–4 h after administration of DE. A specific gas chromatographic method was used for DE assay in plasma and urine. Absorption was rapid in all patients. Urinary excretion during the first 48 h after drug intake varied between 35 and 75%. The lowest effective antiarrhythmic concentration estimated in six patients ranged from 1.4 to 7.0 µg/ml. β-Phase half-life in five patients was between 10.3 and 22.1 h.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00562898
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  • 74
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    Electronic Resource
    Dose-dependence of the pharmacokinetics of quinidine (1977)
    Springer
    European journal of clinical pharmacology 12 (1977), S. 73-76 
    Details
    ISSN: 1432-1041
    Keywords: Quinidine ; pharmacokinetics ; non-linearity ; dose-dependent pharmacokinetics ; steady state plasma level ; oral administration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Quinidine was administrated orally to five healthy male volunteers. Doses of 0.2 g t. i. d., 0.3 g t. i. d. and 0.4 g t. i. d. were given for five days with at least four weeks between each test period. The plasma concentration of quinidine was measured before the morning dose on Days 2–5 of treatment, and 1, 2, 4 and 8 h after the morning dose on the 5th day. There was not a linear relationship between the increase in dose and the increase in plasma concentration of quinidine. A dose increase of 50% from 0.6 to 0.9 g quinidine sulphate per day resulted in an increase in steady state concentration of 94%. A further 33% increase in dose, from 0.9 to 1.2 g daily, resulted in a 55% increase in the steady stae concentration of quinidine. The results demonstrate dose-dependent pharmacokinetics for quinidine. Possible explanations for the nonlinear pharmacokinetics are discussed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00561409
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  • 75
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    Electronic Resource
    Pharmacokinetics of methyldopa in healthy man (1977)
    Springer
    European journal of clinical pharmacology 12 (1977), S. 117-123 
    Details
    ISSN: 1432-1041
    Keywords: Methyldopa ; radioactive label ; pharmacokinetics ; metabolism ; healthy volunteers ; intravenous and oral administration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of 2-14C-L-α-methyldopa have been investigated in five healthy volunteers following intravenous and oral administration. In the intravenous study a bi-phasic plasma concentration curve was found both for chemically determined α-methyldopa and for radioactivity. The plasma level of radioactivity differed significantly from chemically determined drug, a pattern which was also found in urine. This suggests the presence of unidentified metabolite(s). The difference between plasma disappearance and urine recovery of α-methyldopa and radioactivity during the first 4 h after injection suggests distribution to an extravascular compartment. Plasma half-lives of total radioactivity and of unchanged drug were calculated. In three subjects, pharmacokinetic parameters for a two-compartment open body model were calculated from urine and plasma data. Urinary recovery of radioactivity was almost complete within 48 h after intravenous administration. After oral administration, however, only about 40 per cent of the radioactive dose was recovered in the urine, and it contained approximately equal amounts of unconjugated methyldopa, acid-labile conjugated methyldopa and unidentified metabolite(s). The acid-labile conjugate was found only after oral administration, which supports the theory of a mucosal conjugation process. The lack of acid-labile conjugated drug either in the plasma or urine after intravenous injection indicates that there is no enterohepatic circulation of this drug.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00645132
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  • 76
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    Electronic Resource
    Pharmacokinetics of paracetamol (acetaminophen) after intravenous and oral administration (1977)
    Springer
    European journal of clinical pharmacology 11 (1977), S. 283-286 
    Details
    ISSN: 1432-1041
    Keywords: Paracetamol ; Acetaminophen ; pharmacokinetics ; first-pass elimination ; intravenous administration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Plasma paracetamol concentrations were measured in 6 volunteers after single intravenous (1000 mg) and oral (500 mg, 1000 mg and 2000 mg) doses of the drug. Paracetamol levels declined multiphasically with a mean clearance after intravenous administration of 352±40 ml/min. A two-compartment open model appeared to describe the decline adequately. Comparison of the areas under the plasma concentration-time curves (AUC) indicated that oral bioavailability increased from 0.63±0.02 after 500 mg, to 0.89±0.04 and 0.87±0.08 after 1000 mg and 2000 mg, respectively. As a consequence of the incomplete bioavailability of paracetamol, as well as its multicompartmental distribution, accurate estimates of its distribution volume and clearance cannot be obtained if the drug is given orally. However, an estimate of its total plasma clearance may be derived from the AUC after a 500 mg oral dose.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00607678
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  • 77
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    Electronic Resource
    Distribution and elimination of digoxin in infants (1977)
    Springer
    European journal of clinical pharmacology 11 (1977), S. 329-335 
    Details
    ISSN: 1432-1041
    Keywords: Digoxin ; pharmacokinetics ; two-compartment model ; radioimmunoassay ; neonates ; infants
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The distribution and elimination of intravenous digoxin were investigated in seven neonates and infants with heart failure. Serum digoxin concentrations during a 24 h period were determined by radioimmunoassay, using125I as tracer. The serum values declined biexponentially after the injection and could be fitted to a two-compartment open model by non-linear least-squares regression. The calculated mean half-lives of the distribution (alpha) phase in neonates and infants were 37 and 28 min, respectively. The mean half-life of the elimination (beta) phase in neonates was 44 h, as compared to 19 h in infants. The mean volume of the central compartment and the mean volume of distribution at steady-state were calculated to be 1.3 and 9.9 l/kg, respectively; no significant differences between neonates and infants were found. The relation between these volumes indicates that digoxin is extensively distributed in tissues. The steady-state distribution volumes of digoxin in neonates and infants exceed those reported in adults. The larger volume of distribution might explain in part why infants with cardiac insufficiency require larger doses of digoxin than adults (on a mg/kg body weight basis) to obtain the same serum concentrations. Elimination of digoxin from the body was slower in neonates than in infants.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00566529
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  • 78
    Electronic Resource
    Electronic Resource
    Individual variation in the response to phenprocoumon (1977)
    Springer
    European journal of clinical pharmacology 11 (1977), S. 351-358 
    Details
    ISSN: 1432-1041
    Keywords: Phenprocoumon ; protein binding ; pharmacokinetics ; pharmacodynamics ; drug therapy ; myocardial infarction ; chronic disease
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In nine patients, the synthesis rate Rsyn of the vitamin K-dependent clotting factors was calculated from changes in prothrombin-complex activity after intravenous administration of a synthesis-blocking dose of phenprocoumon (PPC). The biological half-life of PPC was between 2.70 and 7.01 days. No correlation was found between the level of the free fraction of this strongly protein-bound drug and its biological half-life. There was a positive correlation (p〈0.01) between the size of the free fraction of PPC and the apparent volume of distribution of the drug. Four of the patients had had an acute myocardial infarction and they showed increased sensitivity to PPC. In them the plasma level of PPC sufficient to reduce Rsyn to 50% of R°syn was significantly lower, and the depression of individual vitamin K-dependent coagulation factors was more pronounced and prolonged, than in five other patients with chronic disease. The degradation rate of coagulation factors was also found to be higher in the patients with acute myocardial infarction. In four patients with chronic disease, anticoagulant therapy with PPC was continued in the out-patient clinic. The calculated oral maintenance dose of PPC, assuming complete absorption, first-order elimination kinetics and a linear relationship between the pharmacological effect and the logarithm of the PPC-plasma concentration, showed good agreement with the dose actually found to produce the desired PP% level.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00566532
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  • 79
    Electronic Resource
    Electronic Resource
    Biotransformation and pharmacokinetics of acenocoumarol (Sintrom®) in man (1977)
    Springer
    European journal of clinical pharmacology 11 (1977), S. 367-375 
    Details
    ISSN: 1432-1041
    Keywords: Acenocoumarol ; excretory balance man ; pharmacokinetics ; biotransformation ; plasma protein binding
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The absorption, biotransformation and elimination of the anticoagulant acenocoumarol, 3-[α- (4′-nitrophenyl)-β-acetylethyl]-4-hydroxycoumarin, have been studied by oral administration of 12 mg of a14C-labelled preparation to two male volunteers. Absorption from the gastro-intestinal tract was rapid and the plasma concentration of unchanged drug reached a maximum of 169 and 412 ng/ml, respectively, after 3 hours. The elimination half-life in the two subjects, calculated from the decline between 6 and 24 h, was 8.7 and 8.2 hours. A constant proportion of 98.7% of the drug was bound in vitro to serum proteins over a concentration range of 0.021–8.34 µg/ml, with little interindividual variation. The major portion of the binding was to human serum albumin (97.5%) at two classes of binding sites: association constant K1=1.04×105 l/mole (n1=1) and K2=5.55×103 l/mole (n2=4). In addition to unchanged acenocoumarol, four metabolites were determined in plasma by isotope dilution techniques: the amino-, acetamido-, alcohol1- and alcohol2-metabolites. Of them, the amino-metabolite showed the highest concentration, namely 278 ng/ml, after 6 h in Subject A, and 163 ng/ml after 10 hours in Subject B. Judged from the integrated concentrations, the compounds analyzed accounted for 76 and 89%, respectively, of the total radioactivity in plasma. All the metabolites detected in plasma showed anticoagulant activity when tested in mice. The quantities of the metabolites excreted in urine from 0–120 hours were (Subject A/Subject B): acenocoumarol 0.3/0.2%, amino-metabolite 12.3/7.7%, acetamido-metabolite 19.0/11.1%, alcohol1-metabolite 4.6/9.0%, alcohol2-metabolite 1.7/4.4%, 6-hydroxy-metabolite 6.9/18.3% and 7-hydroxy-metabolite 14.0/22.2%.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00566534
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  • 80
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    Electronic Resource
    Pharmacokinetics of hydrochlorothiazide in man (1977)
    Springer
    European journal of clinical pharmacology 12 (1977), S. 297-303 
    Details
    ISSN: 1432-1041
    Keywords: Hydrochlorothiazide ; pharmacokinetics ; dose/response relationship ; natriuresis ; kaliuresis ; calciuresis ; magnesiuresis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Hydrochlorothiazide (hct) was administered orally in four different doses (12.5, 25, 50 and 75 mg), to eight healthy volunteers. Plasma and urine concentrations of hct were determined by GLC. Maximal plasma levels were found at 1.5–5 h, and averaged 70, 142, 260 and 376 ng × ml−1 respectively. The peak plasma levels and AUC0→9h of hct were highly correlated (p〈0.001) with the dose. The decline in the plasma curve was biphasic in those experiments in which the plasma levels of hct could be determined for at least 24 h. The half life of the slower phase lay between 5.6 and 14.8 h. The urinary recovery of hct, which represented the gastrointestinal absorption, averaged 65 to 72 per cent of the dose. The mean renal plasma clearance did not vary with the dose and averaged 319 to 345 ml × min−1. The diuresis during the 10 h after hct 12.5 mg exceeded that after placebo by a mean of 800 ml. The diureses was not increased further after higher doses of hct. The maximal natriuretic effect (+ 100 mmol), too, was found after the 12.5 mg dose. The excretion of potassium, however, rose with increasing doses; the maximal increment, after 75 mg hct, averaged 25 mmol. The excretion of calcium was significantly increased after 50 mg hct (+ 0.6 mmol). The maximal effect on magnesium excretion occurred after 25 mg hct (+ 0.5 mmol). In healthy volunteers there was no correlation between peak plasma level of hct or AUC0→9h and the renal excretion of water and electrolytes.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00607430
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  • 81
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    Electronic Resource
    Pharmacokinetics of phenobarbital in childhood (1977)
    Springer
    European journal of clinical pharmacology 12 (1977), S. 305-310 
    Details
    ISSN: 1432-1041
    Keywords: Phenobarbital ; pharmacokinetics ; neonates ; infancy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In 14 neonates 1–4 weeks old, 30 babies aged 1–12 months, and 7 infants of 1–5 years of age, the serum levels of phenobarbital were determined by a gas chromatographic micro-method after intravenous injection of phenobarbital 5–10 mg per kg body weight. It was possible to calculate the pharmacokinetic parameters using a two compartment open model. The distribution volumes within the individual age groups and the rate constants k12 and k21 showed no significant differences, but the elimination half-life was significantly longer in neonates (118.6±16.1 h) than in babies (62.9±5.2 h) or infants (68.5±3.2 h).
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00607431
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  • 82
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    Electronic Resource
    Pharmacokinetics of tolmetin with and without concomitant administration of antacid in man (1977)
    Springer
    European journal of clinical pharmacology 12 (1977), S. 421-428 
    Details
    ISSN: 1432-1041
    Keywords: Tolmetin ; pharmacokinetics ; bioavailability ; antacid ; oral dose
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The purpose of this study was to determine whether a concomitant single dose of antacid or multiple doses of antacid administered prior to, and with tolmetin, alter the pharmacokinetics of tolmetin when the drug was administered as a commercially available tablet containing tolmetin sodium. The possible effects of the antacid on plasma concentrations and urinary excretion of tolmetin and its major metabolite were evaluated following administration of: (a) tolmetin sodium alone; (b) antacid four time a day for three days prior to a single dose of tolmetin sodium, with continuation of the antacid during the day tolmetin was given; and (c) co-administration of single doses of tolmetin sodium and antacid. The twenty-four subject study was of the crossover type. There were no significant differences among treatment means for: (i) peak plasma concentrations of both tolmetin and metabolite, (ii) AUC 0–8 h and AUC 0-∞ for both tolmetin and metabolite, (iii) time to peak plasma concentration for both tolmetin and metabolite, (iv) plasma concentrations of both tolmetin and the metabolite at all sampling times (except for tolmetin at 2 h), (v) renal clearance of both tolmetin and its metabolite, and (vi) the amount of metabolite excreted in the 0–24 h urine. There were small, but significant, differences among amounts of tolmetin excreted in the 0–24 h urine. Semilogarithmic plots of both tolmetin and metabolite plasma concentrations past the peak concentrations were curved over the entire 8-h observation period; although the elimination half-life of tolmetin has been reported to be about one hour, the half-life most probably exceeds 2.6 h in most subjects. The results of this study indicate a lack of a significant drug-drug interaction between the non-steroidal anti-inflammatory agent, tolmetin sodium, and a commonly used antacid, which is a mixture of magnesium and aluminium hydroxides.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00561061
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  • 83
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    Electronic Resource
    Curve fitting and modeling in pharmacokinetics and some practical experiences with NONLIN and a new program FUNFIT (1977)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 5 (1977), S. 513-531 
    Details
    ISSN: 1573-8744
    Keywords: pharmacokinetics ; nonlinear regression ; curve fitting ; computer program ; time sharing ; modeling ; weighting ; least squares ; parameter estimation ; discrimination between models
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The problems of curve fitting and modeling in pharmacokinetics are discussed. A new nonlinear regression program FUNFIT, written for interactive time sharing, is presented which should be more reliable than programs based on the Gauss-Newton or other related gradient methods. The new program and the well-established program NONLIN were tested on two linear models using human plasma drug level data. FUNFIT found a substantially better solution than NONLIN in the majority of the cases.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01061732
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  • 84
    Electronic Resource
    Electronic Resource
    Influence of sampling on drug kinetics in liver perfusion (1977)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 5 (1977), S. 335-358 
    Details
    ISSN: 1573-8744
    Keywords: pharmacokinetics ; perfusion models ; sampling ; parameter estimation ; computer program ; Org GB 94 ; mianserin ; Org GC 94
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract A mathematical treatment of the influence of sampling on drug kinetics in liver perfusion is presented. Based on the derived equations, a Fortran IV computer program (PERFUS) is given, by which the time course of drug concentrations can be simulated for any sampling scheme. The simulations show that the withdrawal of large samples from the reservoir, i.e., larger than 5% of the reservoir volume, results in substantially biased parameters for drugs that are rapidly distributed and/or metabolized. For the fitting of empirical data, a Fortran IV computer program is given, based on BMDX85 nonlinear least squares by Gauss-Newton iterations. This program (PERFIT) estimates model parameters corrected as if no sampling had occurred, no matter how distorted the drug disappearance curve mày be as a result of sampling or due to degeneration of the two-compartment model into a one-compartment model. The conditions under which this degeneration occurs are discussed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01061695
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  • 85
    Electronic Resource
    Electronic Resource
    Hepatic clearance of local anesthetics in man (1977)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 5 (1977), S. 111-122 
    Details
    ISSN: 1573-8744
    Keywords: hepatic clearance ; extraction ratio ; local anesthetics ; pharmacokinetics ; lidocaine ; bupivacaine ; etidocaine ; cardiovascular effects of local anesthetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Two independent methods of calculating hepatic drug clearance were applied to data from studies of the human pharmacokinetics of lidocaine, bupivacaine, and etidocaine. Within experimental limitations, agreement was good between estimates obtained by measurement of areas under blood drug concentration-time curves after rapid intravenous injection and by direct measurement of arterial and hepatic venous drug concentrations. Apparent hepatic extraction ratios of the agents followed the order etidocaine (∼0.73)/s〉lidocaine (∼0.68〉bupivacaine (∼0.37).Pharmacokinetic implications of increases in hepatic blood flow induced by the agents are discussed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01066215
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  • 86
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    Electronic Resource
    Pharmacokinetic and biopharmaceutic profile of chlordiazepoxide HCl in healthy subjects: Single-dose studies by the intravenous, intramuscular, and oral routes (1977)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 5 (1977), S. 3-23 
    Details
    ISSN: 1573-8744
    Keywords: chlordiazepoxide ; benzodiazepine ; two-compartment model, biopharmaceutics ; pharmacokinetics ; single dose ; routes of administration ; intravenous ; intramuscular ; oral
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Single 30- mg doses of chlordiazepoxide HCl were administered to six healthy human subjects by the intravenous, oral, and intramuscular routes. Plasma concentration- time curves following intravenous administration were satisfactorily described by a biexponential equation consistent with a two-compartment open model system. Mean values of half-lives for the so-called distribution and elimination phases were 0.252 and 9.39 hr, respectively. The mean values for the volume of the central compartment (V 1) and volume of distribution $$(V_{d_\beta } )$$ were 18.0 and 30.9% of body weight, respectively. Following oral administration, the drug was rapidly and completely absorbed. Absorption was first order (t1/2≈27 min), and three of the six subjects showed a discernible lag time of approximately 20 min. Drug absorption following intramuscular administration was comparatively slow. A two- compartment “muscle model” comprised of precipitated and solubilized drug in the muscle was found to satisfactorily characterize the absorption process following administration by this route.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01064806
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  • 87
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    Electronic Resource
    A pharmacokinetic model for high-dose methotrexate infusions in man (1977)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 5 (1977), S. 421-433 
    Details
    ISSN: 1573-8744
    Keywords: methotrexate ; pharmacokinetics ; model ; computer ; cancer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The infusion of high doses of methotrexate followed by folinic acid rescue is clinically useful against a variety of tumors. We studied the plasma pharmacokinetics of high-dose methotrexate infusions in patients with advanced cancer and devised a compartmental, kinetic model. our model is based on an earlier, mathematical model which describes the pharmacokinetics of moderate- to- high-dose methotrexate given as a single, intravenous injection. Mathematical equations for our model were solved on a UNIVAC1108 computer with the SAAM program. Seven compartments represent the distribution spaces for methotrexate and its metabolites. The transport of drug into and out of compartments is described by first-order differential equations. A nonlinear, concentration-dependent function is used for renal excretion with saturation of secretory and reabsorption mechanisms by methotrexate. Our model accurately depicts the pharmacokinetics of nine courses of therapy in five patients. The model can also be used to simulate the kinetics of methotrexate for patients with impaired renal function.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01061726
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  • 88
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    Electronic Resource
    Gentamicin disposition and tissue accumulation on multiple dosing (1977)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 5 (1977), S. 559-577 
    Details
    ISSN: 1573-8744
    Keywords: gentamicin ; tissue distribution ; pharmacokinetics ; two-compartment modeling
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Gentamicin pharmacokinetics was examined in a group of 47 patients with stable renal function treated an average of 10 days for severe infection. Serum concentrations rose continually during treatment, and declined in two phases after the drug was stopped, with a mean half-life of 112hr (range 27–693 hr) in the second phase. A two-compartment model was used to describe the biphasic decline in serum concentrations and to calculate the amount of drug in the tissue compartment at all times during and after treatment. Predicted tissue amounts of gentamicin rose continually on multiple dosing in all patients. In six patients who died, postmortem tissues were obtained to quantitate recovery. In all cases, the predicted amount of gentamicin in tissues was in close agreement with the amount recovered at autopsy. Tissue distribution and accumulation constitute a major reason for variability in gentamicin pharmacokinetics and explain both the rising peak and trough serum concentrations and the prolonged detection of gentamicin in serum and urine after the drug is stopped.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01059684
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  • 89
    Electronic Resource
    Electronic Resource
    Pharmacokinetic and biopharmaceutic profile of chlordiazepoxide HCl in healthy subjects: Multiple-dose oral administration (1977)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 5 (1977), S. 25-39 
    Details
    ISSN: 1573-8744
    Keywords: chlordiazepoxide ; benzodiazepine ; two-compartment model ; multiple dosing ; pharmacokinetics ; biopharmaceutics ; metabolism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Eight healthy male volunteers received chlordiazepoxide HCl orally at a dosage of 10 mg every 8 hr over a period of 21 days. On day 22, the regimen was changed to 30 mg every 24 hr for an additional 15 days. Plasma concentrations of chlordiazepoxide and its metabolites desmethyl-chlordiazepoxide, demoxepam, and desoxydemoxepam were measured during 14 of the 36 treatment days. Chlordiazepoxide plasma concentration- time data were consistent with first-order absorption and complete bioavailability. The harmonic mean absorption half-life was 12.3 min. Disposition of chlordiazepoxide was described by a two-compartment open model with a harmonic mean terminal exponential half-life of 10.1 hr. Average steady — state plasma levels of chlordiazepoxide, desmethylchlordiazepoxide, and demoxepam were approximately 0.75, 0.54, and 0.36 μg/ml, respectively.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01064807
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