ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION OF ATEVIRDINE IN THE RAT

Atevirdine mesylate (U-87201E) is a highly specific nonnucleoside inhi bitor of human immunodeficiency virus type 1 reverse transcriptase. Th e absorption, metabolism, and excretion of atevirdine were investigate d 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 [C-14]atevirdine mesylate single doses of 10 mg/kg or 100 mg/kg on study days 1 and 10. The distribution of [C-14]a tevirdine mesylate was also evaluated by whole-body autoradiography in male and female Sprague-Dawley, pregnant Sprague-Dawley, and male Lon g-Evans rats after a single 10 mg/kg oral dose. Plasma levels of atevi rdine and its N-desethyl and O-desmethyl metabolites were determined b y high-performance liquid chromatography (HPLC) with ultraviolet detec tion, urine and feces were profiled for atevirdine and metabolites by HPLC with radiochemical detection, major metabolites in urine were iso lated and identified by nuclear magnetic resonance and mass spectromet ry, and minor urinary metabolites were identified by liquid chromatogr aphy/mass spectrometry. Atevirdine was rapidly absorbed. The pharmacok inetics of atevirdine were nonlinear. Gender differences in the pharma cokinetics 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 transfe r. 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 dose s. 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.