The pharmacokinetics and relative bioavailability of butriptyline from conventional and a sustained release (SR) formulation have been studied in a panel of 14 volunteers. A single oral dose of 75 mg butriptyline hydrochloride was administered and a 2 X 2 latin square design was followed. Pharmacokinetic modelling has shown that the plasma butriptyline concentration/time profile is adequately described by a two-compartment open model; good agreement was obtained for the model-fitted and measured parameters. The SR formulation was shown to possess sustained release characteristics as evidenced by the increase in Tmax for 2.6 to 7.5 h, the decrease in Cmax from 46.5 to 10.3 ng ml-1, and a three-fold increase in 'half-value duration' (HVD). The changes have been achieved without any significant decrease in the relative bioavailability of the SR formulation. The half-life of butriptyline in plasma was about 20 h and was not formulation dependent.

Adult↗

PubMedDate not supplied

Biopharmaceutical characteristics of a new propranolol/hydrochlorothiazide tablet combination.

Experiments have been carried out in dogs and man to determine the effect of hydrochlorothiazide (HCT) on the pharmacokinetics of propranolol and to evaluate the bioavailability of two dosage forms containing both propranolol and HCT (40/25 and 80/25 mg, respectively). In adult male beagles, 50 mg of HCT had no apparent effect on AUC, Cmax, Tmax, and T1/2 of propranolol administered concurrently. In man, INDERIDE (40/25 mg) and INDERIDE (80/25 mg) were shown to be similar in bioavailability to the reference formulations, i.e. the same amount of drugs administered as the separate tablets of INDERAL plus HYDRODIURIL.

Adolescent↗

PubMedDate not supplied

Bioavailability studies with etodolac in dogs and man.

The effects of formulation, particle size, coadministration of food, antacids, or antiulcer agents on the bioavailability of etodolac (ULTRADOL, 1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid), a novel non-steroidal anti-inflammatory agent, have been evaluated in dogs and man. The effects of dosage regimen and/or repetitive dosing on bioavailability were also determined. In man, capsule and tablet dosage forms containing micronized etodolac were shown to have a bioavailability (AUC) equal to that of the reference etodolac solution. Etodolac from tablets and capsules was rapidly absorbed since only minor decreases in Cmax and increases in tmax were observed compared to the etodolac solution. In a comparison of regular and micronized etodolac dosage forms, both in dogs and man, similar findings, i.e. no change in AUC but small parallel changes in Cmax and tmax, were noted. Administration of etodolac with food had no effect on etodolac bioavailability in dogs but tended to cause a delay in its absorption. Coadministration of an antacid, magaldrate, or the antiulcer agent, sucralfate, had no effect on the bioavailability of etodolac in dogs, although with the latter, a significant reduction in Cmax was noted. In man, etodolac may be administered as a single bolus dose or in divided (b.i.d.) doses without any loss in bioavailability. With either regimen, on repeat administration for 7 days, no etodolac accumulation was noted.

Acetates↗

PubMedDate not supplied

Comparative bioavailability of propranolol: twice-daily versus four times-daily administration.

Nineteen healthy male volunteers were given daily 160 mg propranolol hydrochloride in divided doses, either four 40-mg tablets or two 80-mg tablets, and the plasma propranolol concentration profiles were compared after one and seven consecutive days of drug administration. The results indicate that the relative rate and extent of propranolol absorption were greater after 80 mg given twice daily than after 40 mg given four times per day. Both differences were statistically significant at steady state attained with the seven-day treatment. The variability in the areas under the concentration-time curves of propranolol appeared to be smaller after the 80-mg twice-a-day dosing schedule. The results are in accordance with the observed therapeutic equivalence of the two dosing regimens.

Absorption↗

PubMedDate not supplied

Comparative pharmacodynamics and pharmacokinetics of conventional and long-acting propranolol.

This investigation was conducted to compare the pharmacokinetic and pharmacodynamic effects of single and multiple doses of conventional propranolol and long-acting propranolol in healthy human volunteers. Two double-blind, randomized, double-crossover, Latin square studies were carried out. One study evaluated long-acting propranolol 160 mg/d, conventional propranolol 40 mg qid, or placebo for seven days in 24 men. The other study compared long-acting propranolol 80 mg/d, conventional propranolol 20 mg qid, or placebo for seven days in 27 men. At specific times after the administration, blood samples were obtained, and heart rate and blood pressure were measured; exercise tests were done both on the first day and at steady state (day 7). In both studies, the area under the plasma propranolol concentration-time curve and the peak concentration were significantly less (P less than .0001) after the administration of long-acting propranolol compared with conventional propranolol on both day 1 and day 7; in addition, the elimination half-life was longer after administration of the long-acting preparation (9 hr) compared with that following the conventional dosage form (4 hr). Both conventional and long-acting propranolol significantly decreased the exercise heart rate at each of the selected time points (P less than .05) compared with placebo. Reduction in exercise heart rate was greater with conventional propranolol than with the long-acting formulation, but the differences were not statistically significant, when exercise was performed only at trough levels of the conventional drug. The decreases in exercise heart rate were correlated with plasma propranolol concentrations.

Adolescent↗

PubMedDate not supplied

Metabolic disposition and pharmacokinetics of pelrinone, a new cardiotonic drug, in laboratory animals and man.

The metabolic disposition of pelrinone, a cardiotonic drug, was studied in mouse, rat, rabbit, dog, monkey and man. Pelrinone was rapidly and extensively absorbed in rodents, dogs, monkeys and man. Except in rabbits, the major portion of the serum radioactivity was due to parent drug. Pelrinone was moderately bound to human serum proteins and weakly bound to serum proteins from animals. Radioactive compounds were rapidly eliminated from rat tissues with the highest concentrations found in organs associated with absorption and elimination. After a 1.0 mg/kg i.v. dose, the rapid elimination of pelrinone from mouse, rat and dog serum precluded estimation of an elimination half life (t1/2). However, after higher oral or i.v. doses, a more prolonged elimination phase was apparent and the t1/2 of pelrinone ranged from 8-10 h in rodents and dogs. In human subjects given escalating oral or i.v. doses of pelrinone, the elimination t1/2 was independent of dose and averaged 1-2 h. The serum AUC of pelrinone was linearly dose-related following oral doses up to 20 mg/kg in dogs and 100 mg in man. In mice, a greater proportional increase in AUC occurred between oral doses of 2-100 mg/kg while in rats, the serum AUC increased in less than proportional manner from 10-200 mg/kg p.o. In all species, radioactive compounds were excreted mainly in the urine. No metabolites were detected in dog and human urine while small amounts of unconjugated metabolites were excreted in mouse and rat urine.

Administration, Oral↗

PubMedDate not supplied

Tolrestat pharmacokinetics in rat peripheral nerve.

The clinical efficacy of an aldose reductase (AR) inhibitor in diabetic polyneuropathy depends on its bioavailability at the site(s) of AR in peripheral nerves. Accordingly, the link between the concentration of the AR inhibitor, tolrestat, and the extent of its inhibition of the AR-catalyzed polyol production was investigated in sciatic nerves of galactosemic rats. Tolrestat was administered by gavage (1 x 150 mg/kg, or 5, and 15 mg/kg/day for 15 days to attain steady state as estimated from the 53-h half-life of tolrestat determined in rat nerve); subsequently, at six time intervals, ranging from 4 to 59 days, rats were given access for 4 days to a 20% galactose diet, and killed. At every time point, the composite tolrestat concentration in the nerve correlated with the percentage decrease in nerve galactitol (r = 0.857, p = 0.0015). Because the latter should reflect the extent of nerve AR inhibition by tolrestat, the concentration of "free" tolrestat available at the site(s) of AR in the nerve was estimated from the tolrestat concentration/percent AR inhibition plot obtained in vitro. The estimated amount of tolrestat present at the site(s) of nerve AR represented 0.4% of the composite tolrestat concentration measured in the nerve. The results support the view that the effectiveness of an AR inhibitor in peripheral nerve depends on its pharmacokinetics in the nerve, i.e., on its uptake, nonspecific binding to cellular constituents, and elimination.

Administration, Oral↗

PubMedDate not supplied

Metabolic disposition and pharmacokinetics of the aldose reductase inhibitor tolrestat in rats, dogs, and monkeys.

The metabolic disposition and pharmacokinetics of the aldose reductase inhibitor tolrestat were studied in rats, dogs, and assamese and capuchin monkeys. In addition, the ocular penetration of tolrestat was examined in rabbits. The bioavailability of tolrestat was 81% in rats and 68% in dogs. In contrast to rats, a major proportion of the serum 14C in dogs and monkeys was due to unchanged drug. The terminal elimination half-life of tolrestat in serum was 3.5 hr in rats, 11 hr in dogs, and 9 hr in monkeys; in both dogs and monkeys, the total body clearance was 200 ml/kg X hr, and the volume of distribution was 3 liters/kg. In rats and dogs, serum tolrestat concentrations were similar after single and multiple po doses, and were linearly dose-related up to 25 mg/kg, but increased disproportionately at higher doses. Tolrestat was at least 98% bound to rat and dog serum proteins. Except for organs associated with absorption and elimination, tissue 14C levels were lower than in serum of rats and capuchin monkeys, and there was no tissue 14C accumulation. The 14C from topically applied 14C-tolrestat readily penetrated into the eyes of rabbits. Liver microsomal cytochrome P-450 was virtually unaltered in tolrestat-treated rats. Tolrestat (and/or its metabolites) underwent enterohepatic circulation in rats. Most of the 14C from 14C-tolrestat administered po and iv to rats and dogs was excreted in the feces. Based on 14C excretion, the absorption of tolrestat was 84% in rats and 82% in dogs.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMedDate not supplied

Disposition of furobufen in mice, rats, dogs, and man.

Upon administration of the nonsteroidal anti-inflammatory agent furobufen to mice, rats, dogs, and man, 2-dibenzofuranacetic acid (DBFA) was rapidly formed and was the major circulating metabolite. There was a species difference in the rate of DBFA formation; the serum elimination half-lives (t1/2) of furobufen and DBFA were 25 min and 6 hr in rats, 35 min and 15 hr in dogs, and 3 hr and approximately 20 hr in man, respectively. After oral and intravenous administration of 14C-furobufen to rats and dogs, virtually all of the serum radioactivity was due to furobufen and DBFA. Serum levels of DBFA in rats, dogs, and man increased in proportion to the oral dose. The t1/2 of furobufen and DBFA in man did not appear to be altered by chronic treatment and were the same in both sexes. Furobufen and DBFA were strongly bound to human serum protein (greater than 99%). A method was elaborated to measure serum furobufen and DBFA spectrophotofluorometrically in the presence of salicylates. Serum levels of furobufen and DBFA were lower in rats treated with aspirin; the effect was dependent upon the dose of aspirin. At the doses used, aspirin did not affect serum furobufen and DBFA in dogs and man.

Adult↗