Pharmacokinetics of practolol in renal failure

Summary The effect of renal failure on the excretion of oral doses of practolol has been studied. The plasma half-life increased up to 6.6 times normal and the cumulative urinary excretion of the drug was reduced. There was a linear correlation between the overall elimination rate constant of practolol and inulin and creatinine clearances. A linear correlation was also found between the renal clearances of practolol and inulin. The dose of practolol required for maintenance therapy should be reduced in patients with impaired renal function.The results have been presented in part as a thesis for the M.D. degree of the University of Giessen.     

Pharmacokinetics of albendazole in man

Summary The pharmacokinetics of albendazole were investigated in healthy volunteers and in patients receiving albendazole for treatment of hydatid disease. Unchanged albendazole was below detectable limits in plasma, urine, bile and cyst fluid. The major metabolite present in all fluids was the sulfoxide. Maximum concentrations of albendazole sulfoxide in plasma were very variable, probably due to variable absorption of albendazole.     

Pharmacokinetics of cefroxadin (CGP 9000) in man

The pharmacokinetics of cefroxadin have been studied after the administration of single oral and intravenous doses to healthy volunteers. Cefroxadin was assayed by HPLC. The kinetics in plasma following i.v. administration were described by using a three-compartment model. An additional disposition phase was observed following oral administration that could not be detected after the low i.v. dose. The terminal half-life was 1.03 h. The apparent volume of distribution at the steady state was consistent with a diffusion of the antibiotic in all extracellular fluids. The AUCafter oral administration was linearly related to the dose. The urinary excretion amounted to 95% of the dose with virtually complete absorption of orally administered drug.     

Pharmacokinetics of benzquinamide in man

Using a newly developed sensitive gas chromatograph-mass spectrometer assay for benzquinamide, pharmacokinetics have been determined in man follovnng the administration of intramuscular, oral, and rectal suppository doses. Drug is absorbed most rapidly from the intramuscular dose and least rapidly from suppositories. The mean apparent elimination half-life is 1.0–1.6 hr from all formulations. Benzquinamide is 33–39% bioavailable from the capsule and suppository formulations, relative to the intramuscular formulation. A high correlation between capsule and suppository bioavailabilities suggests that first-pass metabolism may account for at least part of the incomplete availability.     

Duration of beta-receptor blockade after oral administration of LB-46

Summary The duration of beta-receptor blockade after single oral doses of LB-46 has been investigated by the isoproterenol infusion technique. A single 5 mg dose of LB-46 caused beta-receptor blockade lasting for 45 min to about 15 h; the range of action after 10 mg LB-46 orally was 30 min to 24 h. The duration of action of an equipotent dose of alprenolol was shorter. The therapeutic implications of these results are discussed.Visken, Sandoz.     

Pharmacokinetics and bioavailability of indoprofen in man

Summary In a pharmacokinetic study of the new analgesic and anti-inflammatory drug indoprofen, plasma levels and urinary excretion were determined in four healthy volunteers after 100 mg and 200 mg iv, and after 100 mg (capsules) and 200 mg (tablets) oral doses. After iv administration, the mean biological half-life (t1/2 ) was about 2 h (range 1.4 to 3.2 h). The apparent volume of distribution Vd ranged between 11 to 17 % of body weight, indicating its limited extravascular distribution. Most of the drug was excreted in urine as glucuronide and a smaller proportion as unchanged indoprofen: the 24 h urinary excretion of these compounds accounted for 67 to 95 % of an iv dose. Peak plasma levels occurred between 30 and 120 minutes after oral administration of 100 mg as capsules or 200 mg as tablets. The mean biological half-life was about 2 h, as after iv administration. The bioavailability of oral doses was assessed using both plasma levels and urinary excretion data. The absorption of capsules and tablets was practically complete, that of the former being faster.     

Pharmacokinetics of quinidine related to plasma protein binding in man

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 () varied from 0.071 to 0.146 h^–1 (mean 0.113), and apparent volume of distribution (V) varied from 1.39–3.20 l · kg^–1 (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 V (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.     

Relationship between renal function and elimination kinetics of pindolol in man

Summary In view of a previous report suggesting an increased metabolism of the beta-blocking agent pindolol with decreasing renal function in man, the relationship between renal function and the elimination kinetics of pindolol has been re-examined. There is a statistically significant positive correlation between the renal clearances of pindolol and creatinine but there is no correlation between the non-renal clearance of pindolol and the renal clearance of creatinine. Thus, there is no evidence of an increased metabolism (non-renal clearance) of pindolol with decreasing renal function.     

Pharmacokinetics of unlabelled and14C-labelled pindolol in uraemia

Summary The elimination of pindolol in 25 patients with various degrees of renal failure has been studied after an intravenous dose of 3 mg. A linear correlation was not found between the elimination rate of pindolol and the endogenous creatinine clearance, and the half-life of the unchanged drug was independent of the severity of the renal failure. This implies greater metabolism of pindolol in anuric patients and the extrarenal elimination rate constantk _mwas increased. Three patients with severe renal failure were given 3 mg¹⁴C-pindolol. They showed almost constant plasma levels of radio-activity for 6 h and then slow excretion with a half-life of 48 h, because of accumulation of metabolites in the blood. Up to 90% of the metabolites are glucuronides and sulphates which have no beta-blocking or other clinical activity. Thus, to produce beta-adrenergic blockade the same dose of indolol is required in healthy patients as in those with uraemia.     

Pharmacokinetics and side-effects of clonazepam and its 7- amino-metabolite in man

Summary Clonazepam (CNP) and its principal metabolite in plasma, 7-amino-CNP (ACNP), have been investigated in a prospective study of 27 newly diagnosed epileptics and correlated with specified side-effects. At a daily dose of 6 mg, the average plasma levels of both substances were about 50ng/ml, and individual values ranged from 30 to about 80ng/ml. There was a linear correlation between changes in dose and the resulting plasma levels, which indicates first order elimination kinetics. Side-effects were frequent, but neither their severity nor their occurrence could be related to plasma levels or to the rate of increase in plasma concentration of the drug. Three out of five patients who developed serious dysphoria had significantly high CNP levels. The concentration of ACNP was considerably increased in four patients who subsequently suffered from withdrawal symptoms. Drug interaction with diphenylhydantoin, i.e. decreased CNP level, was observed in all five patients who received both compounds. In general it is not yet possible to define an upper limit for the plasma levels of CNP and ACNP at which toxicity occurs. In patients treated with conventional doses of CNP, measurement of plasma concentration is not required, except in special circumstances, because of the lack of correlation between plasma level and side-effects.     

Pharmacokinetics of single and multiple doses of phenytoin in man

Summary Plasma concentration of phenytoin (diphenylhydantoin, DPH) have been studied in 5 volunteers after single oral and iv doses (5.0 mg sodium DPH/kg), and after multiple oral doses (2.0 mg sodium DPH/kg b.i.d. for 12 days). The data were analysed according to a one compartment model. The plasma half-life was 14.5 h±1.2 S.D. after i.v. administration, its apparent volume of distribution varied little (0.52 l/kg±0.04) and its bioavailability ranged between 0.70 and 1.0 (mean 0.87). After oral administration peak plasma concentrations were reached in 4 to 12 h. Elimination curves were slightly convex, probably due to an effect of slow absorption. Steady-state plasma levels varied twofold between individuals after multiple oral doses and exceeded those predicted from the single i.v. dose by 29 to 77%. The discrepancy was considered to be due to transition to dose-dependent kinetics.This is the last paper written in collaboration with Dr. Balzar Alexanderson before his untimely death on 2nd June 1973. We are grateful for the inspiring and fruitful experience of working with him. To honour his memory as a good friend and brilliant clinical pharmacologist a number of papers from our laboratory will be dedicated to him.     

Pharmacokinetics of N-acetylcysteine in man

Summary N-Acetylcysteine was given intravenously and as three fast dissolving and one slow-release formulation, on separate occasions, as a single dose of 600 mg to 10 fasting (5 men and 5 women) healthy volunteers. Blood and urine were sampled for the following 12 h.Renal clearance constituted around 30% of total body clearance, which was 0.21 l/h/kg. Volume of distribution was 0.33 l/kg, consistent with distribution mainly to extracellular water. The late elimination half-life was 2.27 h and the mean residence time 1.62 h.The slow-release tablet resulted in a flattened plasma concentration-time curve typical of slow release formulations, while the other three oral formulations were rapidly absorbed.The oral availability of N-acetylcysteine varied between 6 and 10%, with the slow-release tablet having the lowest and the fast dissolving tablet the highest availability.     

Pharmacokinetics of fenbufen in man

Summary The pharmacokinetics of fenbufen (3.4-biphenylylcarbonyl propionic acid) a new antiinflammatory agent, and its metabolites, -hydroxy-4-biphenylbutyric acid and 4-biphenylacetic acid have been studied after oral administration to seven patients with rheumatoid arthritis. Fenbufen was administered as a single oral dose of 600 mg in hard gelatine capsules. A specific, sensitive gas chromatographic method was used to measure the concentration of the three compounds. A linear two-compartment open model appeared suitable to describe the course of the plasma level of fenbufen with time. This compound appeared in the blood after a lag time of 0.45 h and the peak plasma concentration of 5.97 µg/ml was observed after 1.19 h. The half-life of plasma disappearance was 10.26 h for fenbufen and 10.07 h and at 9.95 h for metabolites II and III, respectively.     

Pharmacokinetics of Intravenously Administered L-5-Hydroxytryptophan in Man

Abstract The pharmacokinetics of 5-hydroxytryptophan were investigated in relation to intravenous administration of single doses of the amino acid (0.2 mg/kg b.wt.) to five patients pretreated for one week with carbidopa, an L-aromatic amino acid decarboxylase inhibitor. The plasma concentration/time lapse of 5-hydroxytryptophan exhibited bi-exponential disposition characteristics and the data obtained could be closely fitted to an open two compartment pharmacokinetic model with elimination taking place from the central compartment. The apparent composite 1. order rate constants α and β were 1.433 hr^-1 ± 0.177 S.D. and 0.113 hi^-1 ± 0.012 hr^-1 S.D., respectively. The biological half-life of 5-hydroxytryptophan under the experimental conditions was thus about 6 hours. The apparent volume of the central compartment, V_c, was found to be 0.336 1 kg^-1 ± 0.059 S.D. and the plasma clearance 0.105 1 hr^-1 kg^-1 ± 0.015 S.D. The derived pharmacokinetic constants were used for doses regimen calculations and predetermination of the plasma concentration/time lapse, during continuous intravenous infusion therapy. Measured plasma concentrations of 5-hydroxytryptophan during infusion deviated by less than 10 per cent from the predicted values. However, the infusions had to be stopped in four of the experiments because the patients became nauseated and vomited after total doses of only 36-128 mg.     

Pharmacokinetics of a novel surface-active agent,purified poloxamer 188, in rat,rabbit, dog and man

Purified poloxamer 188 (PP188) is a non-ionic, block copolymer surfactant that is currently being evaluated clinically in sickle cell disease vaso-occlusive crisis and acute chest syndrome and preclinically in spinal cord injury and muscular dystrophy. This paper describes the pharmacokinetics of PP188 in rats, pregnant rats, pregnant rabbits, dogs and humans. Plasma protein binding interaction studies demonstrated no clinically significant effects on narcotic analgesics, hydroxyurea, warfarin, diazepam or digitoxin, but an increase in free fraction for propranolol. The plasma concentrations increased proportionate with increasing dose in all species tested. Renal clearance accounted for 90% of total plasma clearance in man. A single metabolite was detected and quantified in the plasma from dogs and humans that was cleared more slowly than parent drug. Allometric scaling of plasma clearance and volume of distribution at steady-state (Vss) across species provided good predictions of the pharmacokinetic parameters in humans. Based on the comparative pharmacokinetics of PP188 in rat, rabbit, dog and man, all three animal species were appropriate models for evaluating various aspects of PP188's toxicological profile.     

Simultaneous tubular excretion and reabsorption of pindolol in man

Summary The plasma concentrations of pindolol have been examined following the administration of single doses of 15 mg tablets to eight healthy male subjects. The apparent half-life of elimination in plasma (t_1/2=4.05 h) and in urine (t_1/2=3.21 h) was calculated using conventional pharmacokinetic methods. The renal clearance was estimated by plotting urinary excretion rates versus plasma concentrations; for all subjects these plots were curved. In addition to these graphical estimations, the plasma concentrations of pindolol and the urinary excretion data for each volunteer were simultaneously fitted using a one or two-compartment open body model; a computer program using non-linear regression algorithms was used. This procedure did not give an adequate fit to the data. Another type of data analysis, using a population — based model, permitted us to show that the renal elimination of pindolol in man comprises of two separate processes — tubular secretion and reabsorption, which was partially saturable under the experimental conditions. The theoretical relevance and clinical significance of these findings are discussed.Supported by the Fonds National Suisse de la Recherche Scientifique     

Bioavailability and Pharmacokinetics in Man of Orally Administered Theophylline

Abstract The pharmacokinetics of theophylline after both intravenous and oral administration was investigated in six hospitalized patients with normal renal, hepatic and pulmonary functions. A rather wide range of biological half-lives from about 3–16 hours and plasma clearance values of about 16.5–115 ml kg^-1 hr^-1 were found in the investigated patients, who were from 31 to 73 years of age. The apparent volumes of distribution during the eliminatory β-phase (V_dβ) were within the range 0.394–0.616 1 kg^-1 with a mean value of 0.484 1 kg^-1 ±0.082 S.D., as determined from the intravenous data, and in excellent agreement with the value obtained from the peroral data. Except in one case theophylline exhibited two compartment characteristics after intravenous administration, while the oral data in only one patient showed this pharmacokinetic configuration and had to be analysed according to one-compartment characteristics in the other five subjects. In the oral experiments absorption rate constants of from about 0.57 to 2.17 hr^-1 were found for the administered microparticulate theohylline tablet preparation, Nuelin® from Riker Laboratories. A wide range of lag-times from 0 to 1.32 hours were also demonstrated in the experiments. The systemic availability of theophylline in this preparation varied from 82.8 to 103% as determined on basis of the ratios of areas under the oral and intravenous serum concentration curves. It is conclusively stated that therapeutic plasma concentrations of theophylline probably may be maintained and controlled efficiently with the investigated oral theophylline preparation. Because of the interindividual variability in the biological half-life of the compound monitoring of the serum theophylline concentration is generally advised in order to avoid toxic side effects, in particular in relation to the initial establishment of a therapeutic serum concentration level in the individual subjects to be treated.     

Pharmacokinetics of ticarcillin in man

Summary The excretion of radioactivity has been investigated in 3 healthy volunteers following rapid intravenous administration of 5 g of [³⁵S]-ticarcillin. The radioactive dose was rapidly and completely excreted, since within 4 days 98.5% was recovered, 95% in the urine and 3.5% in faeces. All the urine radioactivity was accounted for as ticarcillin and its penicilloic acid. Plasma and urine samples collected from the volunteers at frequent intervals during the first 6 h of the experiment were assayed for penicillin by an automated chemical method and also for radioactivity. The results obtained by the chemical autoanalyser method were in excellent agreement with the plasma levels of radioactivity. From the data it was possible to calculate the renal clearance of the penicillin, a mean value of 104 ml/min was observed in the 3 volunteers. A further three volunteers were dosed intravenously with a 5 g bolus of non-radiolabelled ticarcillin in a cross-over study with and without predosing with probenecid. Serum samples were analysed by the chemical method for penicillin and the data subjected to pharmacokinetic analysis using a two compartment open model. The results indicate a shift of the distribution equilibrium of ticarcillin from the serum into the peripheral compartment after predosing with probenecid. Furthermore, the mean half-life of ticarcillin in the serum of the three volunteers was significantly increased from 1.3 h to 2.1 h by predosing with probenecid.     

The use of pindolol in the treatment of essential hypertension: a multi-centre assessment

Summary

A multi-centre general practitioner assessment of pindolol, a beta adrenergic blocking drug, was carried out in 464 patients with essential hypertension. The average daily dose was 21 mg and the average period of observation was 15 weeks. Pindolol was shown to be a safe, effective and well tolerated hypotensive agent. In 227 new cases of hypertension, 148 (65.2%) were controlled on pindolol alone, and in 237 previously treated cases of hypertension 91 (38.4 %) were subsequently controlled on pindolol alone. In the remaining cases the addition of a diuretic or other antihypertensive agent was necessary to achieve satisfactory control. The mean blood pressure was lowered from 190/111 mmHg to 154/90 mmHg, a mean fall of 36/21 mmHg. Side-effects were not of a serious nature.