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 (H IV-2), and hepatitis B virus (HBV) in vitro. Owing to the limited aqueous s olubility of DXG, (-)-beta-D-2,6-diaminopurine dioxolane (DAPD), a more wat er-soluble prodrug of DXG, is being developed for clinical use, The purpose of this study was to characterize the pharmacokinetics of DXG after admini stration of DXG and DAPD to rats and monkeys. After intravenous administrat ion of DXG, plasma concentrations of the nucleoside declined in a biexponen tial 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 sp ecies. Steady state volume of distribution of DXG was 2.30 liters/kg in rat s and 1.19 liters/kg in monkeys, After intravenous administration of DAPD t o rats, prodrug concentrations declined with a half-life of 0.37 +/- 0.11 h r, DXG was rapidly generated from DAPD, with approximately 61% of the dose of DAPD being converted to DXG, After administration of I)APD to monkeys, o nly concentrations of metabolite DXG could be determined owing to rapid con version of DAPD to DXG during sample collection. The half-lives of DAPD and DXG after intravenous administration determined from urinary excretion dat a were 0.8 +/- 0.4 and 1.6 +/- 0.2 hr, respectively. Oral bioavailabitity o f DAPD was estimated to be approximately 30%.