Pharmacokinetics of beta-L-2 ',3 '-dideoxy-5-fluorocytidine in rhesus monkeys

beta-L-2',3'-Dideoxy-5-fluorocytidine (beta-L-FddC), a novel cytidine analo g with an unnatural beta-L sugar configuration, has been demonstrated by ou r group and others to exhibit highly selective in vitro activity against hu man immunodeficiency virus types 1 and 2 and hepatitis B virus. This encour aging in vitro antiviral activity prompted us to assess its pharmacokinetic s in rhesus monkeys. Three monkeys were administered an intravenous dose of [H-3]beta-L-FddC at 5 mg/kg of body weight. Following a 3-month washout pe riod, an equivalent oral dose was administered. Plasma and urine samples we re collected at various times for up to 24 h after dosing, and drug levels were quantitated by high-pressure liquid chromatography. Pharmacokinetic pa rameters were obtained on the basis of a two-compartment open model with a first-order elimination from the central compartment. After intravenous adm inistration, the mean peak concentration in plasma (C-max) was 29.8 +/- 10. 5 mu M. Total clearance, steady-state volume of distribution, terminal-phas e plasma half-life (t(1/2 beta)), and mean residence time were 0.7 +/- 0.1 liters/h/kg, 1.3 +/- 0.1 liters/kg, 1.8 +/- 0.2 h, and 1.9 +/- 0.2 h, respe ctively. Approximately 47% +/- 16% of the intravenously administered radioa ctivity was recovered in the urine as the unchanged drug with no apparent m etabolites. beta-L-FddC exhibited a C-max of 3.2 mu M after oral administra tion, with a time to peak drug concentration of approximately 1.5 h and a t (1/2) of 2.2 h, One monkey in the oral administration arm of the study had a significant delay in the absorption of the aqueous administered dose. The absolute bioavailability of orally administered beta-L-FddC ranged from 56 to 66%.