PHARMACOKINETICS, ORAL BIOAVAILABILITY, AND METABOLISM IN MICE AND CYNOMOLGUS MONKEYS OF 5-FLUORO-1-[2-(HYDROXYMETHYL)-1,3-OXATHIOLAN-5-YL]CYTOSINE, AN AGENT ACTIVE AGAINST HUMAN-IMMUNODEFICIENCY-VIRUS AND HUMAN HEPATITIS-B VIRUS

(2'R, 5 5-Fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl] cytosine (5 24W91) is a nucleoside analog with potent anti-human immunodeficiency virus and anti-human hepatitis B virus activities in vitro. The pharma cokinetics and bioavailability of 524W91 after oral dosing were studie d in mice dosed with 10, 100, and 600 mg of 524W91 per kg of body weig ht by the oral and intravenous routes. Cynomolgus monkeys were dosed w ith 10 and 80 mg of 524W91 per kg. In both species, the clearance of 5 24W91 was rapid, via the kidney, and was independent of dose. In monke ys, the total body clearance of 10 mg of 524W91 per kg was 0.7 +/- 0.1 liter/h/kg, and the volume of distribution at steady state was 0.8 +/ - 0.02 liter/kg. The terminal elimination half-life was 1.0 +/- 0.2 h. The absolute bioavailability after oral dosing was 63% +/- 4% at 10 m g/kg. Concentrations of 524W91 in the cerebrospinal fluid were 4% +/- 0.7% of the corresponding levels in plasma. In mice, the total clearan ce of 10 mg of 524W91 per kg was 2.3 liters/kg/h, and the volume of di stribution at steady state was 0.9 liter/kg. Absolute bioavailability in mice after oral dosing was 96% at a dose of 10 mg/kg. The metabolis m of orally administered [6-H-3]524W91 was studied in cynomolgus monke ys at a dose of 80 mg/kg and in mice at a dose of 120 mg/kg. Monkeys e xcreted 41% +/- 6% of the radioactive dose in the 0- to 72-h urine, 33 % +/- 10% in the feces, and 10% +/- 7% in the cage wash. Unchanged 524 W91 was 64% of the total radiolabeled drug recovered in the urine. The major urinary metabolite was a 3'-sulfoxide, constituting 27% of the radiolabeled material in the urine. The glucuronide was a minor urinar y metabolite. 5-Fluorouracil was not detected (less than 0.02% of the dose). Mice dosed orally with 120 mg of [6-H-3]524W91 per kg excreted 67% +/- 7% of the radiolabel in the 0- to 48-h urine. Small amounts of the 3'-sulfoxide and glucuronide metabolites were observed in the uri ne, but 5-fluorouracil was not detected. Good bioavailability after or al dosing and resistance to metabolism recommend 524W91 for further pr eclinical evaluation.