PHARMACOKINETICS OF 1-(2-FLUORO-5-METHYL-BETA-L-ARABINOFURANOSYL) URACIL IN WOODCHUCKS

-(2-Fluoro-5-methyl-beta-L-arabinofuranosyl)uracil (L-FMAU) is a nucle oside analog with potent in vitro activity against hepatitis B virus ( HBV) and Epstein-Barr virus. The purpose of this study was to characte rize the disposition of L-FMAU following oral and intravenous administ ration in the woodchuck animal model, The numerous similarities betwee n woodchuck hepatitis virus and HBV infection justify the use of the w oodchuck as an animal model for preclinical studies of anti-HBV agents in vivo, Woodchucks were given 25 mg of L-FMAU per kg of body weight intravenously and orally, Concentrations of L-FMAU in urine and plasma were determined by high-performance liquid chromatography. Following intravenous administration of 25 mg of L-FMAU per kg to woodchucks, to tal clearance was moderate, averaging 0.23 +/- 0.07 liter/h/kg. Renal clearance and nonrenal clearance averaged 0.13 +/- 0.08 and 0.10 +/- 0 .06 liter/h/kg, respectively, The steady-state volume of distribution averaged 0.99 +/- 0.17 liter/kg, indicative of intracellular distribut ion of the nucleoside, The terminal-phase half-life of L-FMAU followin g intravenous administration averaged 6.2 +/- 2.0 h, and mean residenc e time averaged 4.5 +/- 0.8 h, Absorption of L-FMAU after oral adminis tration was incomplete, and bioavailability was approximately 20%. Con centrations of L-FMAU in plasma remained above the in vitro 50% effect ive concentration of 0.026 mu g/ml for HBV (C.K. Chu, T. Ma, K. Shanmu ganathan, C, Wang, Y, Xiang, S.B. Pai, G.-Q, Yao, J.-P, Sommadossi, an d Y.-C. Cheng, Antimicrob, Agents Chemother, 39:979-981, 1995) for 24 h after both intravenous and oral administration of 25 mg of L-FMAU pe r kg.