Pharmacokinetics of (-)-beta-D-dioxolane guanine and prodrug (-)-beta-D-2,6-diaminopurine dioxolane in rats and monkeys.

(-)-beta-D-Dioxolane guanine (DXG) is a nucleoside analog possessing potent activity against human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2), and hepatitis B virus (HBV) in vitro. Owing to the limited aqueous solubility of DXG, (-)-beta-D-2,6-diaminopurine dioxolane (DAPD), a more water-soluble prodrug of DXG, is being developed for clinical use. The purpose of this study was to characterize the pharmacokinetics of DXG after administration of DXG and DAPD to rats and monkeys. After intravenous administration of DXG, plasma concentrations of the nucleoside declined in a biexponential manner, with a terminal-phase half-life of 0.44 +/- 0.14 hr (mean +/- SD) in rats and 2.3 hr in monkeys. Total clearance of DXG was 4.28 +/- 0.99 liters/hr/kg in rats and 0.72 liters/hr/kg in monkeys. Renal excretion of unchanged DXG accounted for approximately 50% of total clearance in both species. Steady state volume of distribution of DXG was 2.30 liters/kg in rats and 1.19 liters/kg in monkeys. After intravenous administration of DAPD to rats, prodrug concentrations declined with a half-life of 0.37 +/- 0.11 hr. DXG was rapidly generated from DAPD, with approximately 61% of the dose of DAPD being converted to DXG. After administration of DAPD to monkeys, only concentrations of metabolite DXG could be determined owing to rapid conversion of DAPD to DXG during sample collection. The half-lives of DAPD and DXG after intravenous administration determined from urinary excretion data were 0.8 +/- 0.4 and 1.6 +/- 0.2 hr, respectively. Oral bioavailability of DAPD was estimated to be approximately 30%.