Absorption, distribution, metabolism, and excretion of atevirdine in the rat.

Atevirdine mesylate (U-87201E) is a highly specific nonnucleoside inhibitor of human immunodeficiency virus type 1 reverse transcriptase. The absorption, metabolism, and excretion of atevirdine were investigated in male and female Sprague-Dawley rats after oral administration of nonradiolabeled atevirdine mesylate at doses of 20 mg/kg/day or 200 mg/kg/day for 8 days, with [14C]atevirdine mesylate single doses of 10 mg/kg or 100 mg/kg on study days 1 and 10. The distribution of [14C]atevirdine mesylate was also evaluated by whole-body autoradiography in male and female Sprague-Dawley, pregnant Sprague-Dawley, and male Long-Evans rats after a single 10 mg/kg oral dose. Plasma levels of atevirdine and its N-desethyl and O-desmethyl metabolites were determined by high-performance liquid chromatography (HPLC) with ultraviolet detection, urine and feces were profiled for atevirdine and metabolites by HPLC with radiochemical detection, major metabolites in urine were isolated and identified by nuclear magnetic resonance and mass spectrometry, and minor urinary metabolites were identified by liquid chromatography/mass spectrometry. Atevirdine was rapidly absorbed. The pharmacokinetics of atevirdine were nonlinear. Gender differences in the pharmacokinetics and metabolism of atevirdine were observed, consistent with the involvement of cytochrome P450 3A. Atevirdine effectively crossed the blood-brain barrier and had a high rate of maternal-fetal transfer. At the low doses, <2% of the dose was excreted as unchanged parent drug, while atevirdine constituted 9%-25% of the dose at the high doses. The metabolism of atevirdine was extensive in the rat and involved N-deethylation, O-demethylation, hydroxylation at the C-6 position of the indole ring, and hydroxylation of the pyridine ring.

Metabolic fate of tolazamide in man and in the rat.

The metabolic fate of tolazamide, 1-(hexahydroazepin-1-yl)-3-p-tolylsulfonylurea (1), was studied in man and in the rat using tritium-labeled 1. The metabolites were isolated in crystalline form from urine for structure determination. The crystal structure and final molecular structure of one of these, 1-(4-hydroxyhexahydroazepin-1-yl)-3-p-tolylsulfonylurea (5), were determined using single-crystal X-ray techniques. Following oral administration of tritiated tolazamide to male humans, 85% of the radioactivity was excreted in urine during a 5-day period. In addition to being excreted in urine unchanged, tolazamide was metabolized to 1-(hexahydroazepin-1-yl)-3-p-(carboxyphenyl)sulfonylurea (2), p-toluenesulfonamide (3), 1-(hexahydroazepin-1-yl)-3-p-(hydroxymethylphenyl)sulfonylurea (4), 1-(4-hydroxyhexahydroazepin-1-yl)-3-p-tolylsulfonylurea (5) and a labile, unidentified metabolite 6 by man. The relative amounts of these materials excreted in 0-24-h urine collections from eight subjects averaged 7, 17, 26, 10, 25, and 15% for 1-6, respectively. In the female rat, 79% of an orally administered dose of tritiated tolazamide was excreted in urine during a 5-day period as 1-4. The relative amounts of these materials excreted during the 24-h period following administration of tolazamide were 10, 5, 5, and 80% for 1-4, respectively.

Preparation of [14C]colestipol hydrochloride and its disposition in the human, dog and rat.

Colestipol hydrochloride, a polymeric, ion-exchange type, hypocholesterolemic agent, acting by sequestering bile acids, was labeled with carbon-14. The disposition of the labeled material was studied in the human, dog and rat. The extent of absorption from the gastrointestinal tract, as judged by urinary excretion of radioactivity, was very small and correlated well with the contents of water-soluble and dialyzable materials in the colestipol hydrochloride. Results were consistent with the dialyzable material in the drug being the absorbable species.

Metabolism of minoxidil, a new hypotensive agent I: absorption, distribution, and excretion following administration to rats, dogs, and monkeys.

Minoxidil (2,4-diamino-6-piperidinopyrimidine 3-oxide), a potent new hypotensive agent, was 14C-labeled in the 2-position of the pyrimidine ring in 17 percent yield from Ba14CO3. This material was used to study the absorption, distribution, and excretion of the drug in rats, dogs, and monkeys. Following oral administration of a single dose, the drug was rapidly and well absorbed and rapidly eliminated by each species as judged by plasma levels and urinary excretion of unchanged drug and total drug-related materials. Chronic oral administration of the drug at a high level (10 mg/kg) for 30 days slightly increased the rate of clearance of minoxidil and minoxidil-related material from circulation. Water diuresis, resulting from water loading of dogs, caused an even greater increase in the rates of disappearance of the drug and drug-related material. Whole-body autoradiography studies in rats showed that minoxidil was rapidly distributed following its oral and intravenous administration. It was subsequently concentrated, primarily in the excretory system. Minoxidil-related material was detected in aorta walls, but not in the CNS, following both routes of drug administration.