PHARMACOKINETICS, ORAL BIOAVAILABILITY, AND METABOLIC DISPOSITION IN RATS OF 5-FLUORO-1-[2-(HYDROXYMETHYL)-1,3-OXATHIOLAN-5-YL] CYTOSINE, ANUCLEOSIDE ANALOG ACTIVE AGAINST HUMAN-IMMUNODEFICIENCY-VIRUS AND HEPATITIS-B VIRUS

The pharmacokinetics and metabolism of the potent anti-human immunodef iciency virus and anti-hepatitis B virus compound, -1-[2-(hydroxymethy l)-1,3-oxathiolan-5-yl]cytosine (FTC), were investigated in male CD ra ts. Plasma clearance of 10 mg of FTC per kg of body weight was biexpon ential in rats, with a half-life at alpha phase of 4.7 +/- 1.1 min (me an +/- standard deviation) and a half-life at beta phase of 44 +/- 8.8 min (n = 5). The total body clearance of FTC was 1.8 +/- 0.1 liters/h /kg, and the oral bioavailability was 90% +/- 8%. The volume of distri bution at steady state (V(SS)) was 1.5 +/- 0.1 liters/kg. Increasing t he dose to 100 mg/kg slowed clearance to 1.5 +/- 0.2 liters/kg/h, lowe red the V(SS) to 1.2 +/- 0.2 liters/kg, and reduced the oral bioavaila bility to 65% +/- 15%. FTC in the brains of rats was initially less th an 2% of the plasma concentration but increased to 6% by 2 h postdose. Probenecid elevated levels of FTC in plasma as well as in brains but did not alter the brain-to-plasma ratio. The urinary and fecal recover ies of unchanged FTC after a 10-mg/kg intravenous dose were 87% +/- 3% and 5% +/- 1.6%, respectively. After a 10-mg/kg oral dose, respective urinary and fecal recoveries were 70% +/- 2.5% and 25% +/- 1.6%. Two sulfoxides of FTC were observed in the urine, accounting for 0.4% +/- 0.03% and 2.7% +/- 0.2% of the intravenous dose and 0.4% +/- 0.06% and 2.5% +/- 0.3% of the oral dose. Also observed were 5-fluorocytosine, representing 0.4% +/- 0.06% of the intravenous dose and 0.4% +/- 0.07% of the oral dose, and FTC glucuronide, representing 0.7% +/- 0.2% of the oral dose and 0.4% +/- 0.2% of the intravenous dose. Neither deami nated FTC nor 5-fluorouracil was observed in the urine (less than 0.2% of dose). The high oral availability and minimal metabolism of FTC en courage its further preclinical development.