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Biomedical subjects

M N Cayen

Publications and source records attributed to M N Cayen.

65 records · Page 4Linked to original sources
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

Comparative bioavailability of ceftibuten in capsule and suspension forms.

The comparative bioavailability of ceftibuten, a new third-generation cephalosporin antibiotic given orally once daily, in capsule and suspension dosage forms, was assessed in healthy male subjects. In three separate studies, subjects received either a 400-mg dose as a suspension or one laboratory-batch, 400-mg capsule; one laboratory-batch, 400-mg capsule or two laboratory-batch, 200-mg capsules; or one production-batch, 400-mg capsule or two laboratory-batch, 200-mg capsules. Plasma samples were assayed for ceftibuten using high-performance liquid chromatography, and the data were assessed using pharmacokinetic and statistical methods. Confidence intervals for the maximum plasma concentration and the area under the plasma concentration-time curve extrapolated to infinity were within 80% to 125% of guidelines, demonstrating the bioequivalence of the two treatments within each of the three studies. One 400-mg capsule (laboratory or production batch) was bioequivalent to two 200-mg capsules used in a clinical efficacy trial; the 400-mg suspension was bioequivalent to a 400-mg capsule (laboratory batch). Thus we concluded that the capsule and the suspension dosage forms were bioequivalent.

Administration, Oral↗
PubMedDate not supplied

Disposition of 14C-eptifibatide after intravenous administration to healthy men.

Eptifibatide, a synthetic peptide inhibitor of the platelet glycoprotein IIb/IIIa receptor, has been studied as an antithrombotic agent in a variety of acute ischemic coronary syndromes. The purpose of the present study was to characterize the disposition of 14C-eptifibatide in man after a single intravenous (i.v.) bolus dose. 14C-Eptifibatide (approximately 50 microCi) was administered to eight healthy men as a single 135-microgram/kg i.v. bolus. Blood, breath carbon dioxide, urine, and fecal samples were collected for up to 72 hours postdose and analyzed for radioactivity by liquid scintillation spectrometry. Plasma and urine samples were also assayed by liquid chromatography with mass spectrometry for eptifibatide and deamidated eptifibatide (DE). Mean (+/- SD) peak plasma eptifibatide concentrations of 879 +/- 251 ng/mL were achieved at the first sampling time (5 minutes), and concentrations then generally declined biexponentially, with a mean distribution half-life of 5 +/- 2.5 minutes and a mean terminal elimination half-life of 1.13 +/- 0.17 hours. Plasma eptifibatide concentrations and radioactivity declined in parallel, with most of the radioactivity (82.4%) attributed to eptifibatide. A total of approximately 73% of administered radioactivity was recovered in the 72-hour period following 14C-eptifibatide dosing. The primary route of elimination was urinary (98% of the total recovered radioactivity), whereas fecal (1.5%) and breath (0.8%) excretion was small. Eptifibatide is cleared by both renal and nonrenal mechanisms, with renal clearance accounting for approximately 40% of total body clearance. Within the first 24 hours, the drug is primarily excreted in the urine as unmodified eptifibatide (34%), DE (19%), and more polar metabolites (13%).

Adult↗
PubMedDate not supplied

Pharmacokinetics of intramuscularly administered isepamicin in man.

The pharmacokinetics of isepamicin, a broad-spectrum aminoglycoside antibiotic, was studied in man after intramuscular administration. Two groups each of 6 volunteers received isepamicin for 10 consecutive days by intramuscular injection at respective doses of 7.5 mg/kg once daily or 7.5 mg/kg twice daily. Plasma and urinary concentrations of isepamicin were determined using a specific HPLC method. In both groups, there was no drug accumulation following multiple administration. The t1/2, which ranged from 2.4 to 2.7 h, was independent of the dosage regimen. Isepamicin excreted into (0-24 h) urine accounted for virtually 100% of the dose. The results show that the pharmacokinetics of isepamicin are similar with these dosage regimens. The drug undergoes no detectable biotransformation, does not accumulate upon multiple dosing, and is cleared solely by urinary excretion.

Adolescent↗
PubMedDate not supplied

Considerations in the design of toxicokinetic programs.

The objectives of toxicokinetic (TK) studies are to evaluate systemic exposure of the toxicity species to drug and/or metabolite(s) and to relate exposure to dose level and toxicological findings. The tacit assumption is that such exposure can be related to target organ toxicity. Planning a TK program involves early development (often during discovery support) of an appropriate plasma assay, assurance that the studies conform to Good Laboratory Practices, evaluating exposure at steady state, and effective collaboration among toxicologists, kineticists, and other relevant disciplines. The 3 types of TK studies--prospective, concomitant, and retrospective--each have different goals. The various stages of TK program implementation range from those during drug discovery and selection to support of chronic toxicity studies. Exposure is best expressed as the area under the plasma concentration/time curve of drug and/or metabolite(s) and, for highly protein bound drugs, is based on the unbound fraction. Although the objectives of TK programs are generally standard and the Second International Conference on Harmonization has developed TK guidelines, the programs differ among pharmaceutical companies. Some variables in program design and implementation include properties of the drug, formulation used, characteristics of the target species, ability to develop a toxicokinetic-toxicodynamic relationship, strategies based on scientific/technical/philosophical considerations, dedicated resources, corporate support, and effectiveness of interdepartmental collaborations.

Animals↗
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↗
PubMedDate not supplied

Distribution and excretion of furobufen in rats and dogs.

Groups of male rats and dogs were given single doses of 50 mg of 14C-furobufen per kg orally or intravenously. In rats, tissue radioactivity levels were generally lower than that of serum. Radioactivity accumulated in and was retained by white adipose tissue. The radioactivity in fat was due to a conjugate of dibenzofuranacetic acid, the major metabolite of furobufen. Approximately one-half of the dose was excreted each in the urine and feces of rats after oral and intravenous administration of 14C-furobufen. A similar excretion pattern was observed in dogs after an oral dose.

Adipose Tissue↗