Pharmacokinetics of β-l-2′,3′-Dideoxy-5-Fluorocytidine in Rhesus Monkeys

β-l-2′,3′-Dideoxy-5-fluorocytidine (β-l-FddC), a novel cytidine analog with an unnatural β-l sugar configuration, has been demonstrated by our group and others to exhibit highly selective in vitro activity against human immunodeficiency virus types 1 and 2 and hepatitis B virus. This encouraging in vitro antiviral activity prompted us to assess its pharmacokinetics in rhesus monkeys. Three monkeys were administered an intravenous dose of [(3)H]β-L-FddC at 5 mg/kg of body weight. Following a 3-month washout period, an equivalent oral dose was administered. Plasma and urine samples were collected at various times for up to 24 h after dosing, and drug levels were quantitated by high-pressure liquid chromatography. Pharmacokinetic parameters were obtained on the basis of a two-compartment open model with a first-order elimination from the central compartment. After intravenous administration, the mean peak concentration in plasma (C(max)) was 29.8 ± 10.5 μM. Total clearance, steady-state volume of distribution, terminal-phase plasma half-life (t(1/2β)), 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, respectively. Approximately 47% ± 16% of the intravenously administered radioactivity was recovered in the urine as the unchanged drug with no apparent metabolites. β-l-FddC exhibited a C(max) of 3.2 μM after oral administration, 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 β-l-FddC ranged from 56 to 66%.