Pharmacology and Pharmacokinetics of the Antiviral Agent β- d -2′,3′-Dideoxy-3′-Oxa-5-Fluorocytidine in Cells and Rhesus Monkeys

Abstract

ABSTRACT β- d -2′,3′-Dideoxy-3′-oxa-5-fluorocytidine ( d -FDOC) is an effective inhibitor of human immunodeficiency virus 1 (HIV-1) and HIV-2, simian immunodeficiency virus, and hepatitis B virus (HBV) in vitro. The purpose of this study was to evaluate the intracellular metabolism of d -FDOC in human hepatoma (HepG2), human T-cell lymphoma (CEM), and primary human peripheral blood mononuclear (PBM) cells by using tritiated compound. By 24 h, the levels of d -FDOC-triphosphate ( d -FDOC-TP) were 2.8 ± 0.4, 6.7 ± 2.3, and 2.0 ± 0.1 pmol/10 6 cells in HepG2, CEM, and primary human PBM cells, respectively. Intracellular d -FDOC-TP concentrations remained greater than the 50% inhibitory concentration for HIV-1 reverse transcriptase for up to 24 h after removal of the drug from cell cultures. In addition to d -FDOC-monophosphate ( d -FDOC-MP), -diphosphate ( d -FDOC-DP), and -TP, d -FDOC-DP-ethanolamine and d -FDOC-DP-choline were detected in all cell extracts as major intracellular metabolites. d -FDOC was not a substrate for Escherichia coli thymidine phosphorylase. No toxicity was observed in mice given d -FDOC intraperitoneally for 6 days up to a dose of 100 mg/kg per day. Pharmacokinetic studies in rhesus monkeys indicated that d -FDOC has a t 1/2 of 2.1 h in plasma and an oral bioavailability of 38%. The nucleoside was excreted unchanged primary in the urine, and no metabolites were detected in plasma or urine. These results suggest that further safety and pharmacological studies are warranted to assess the potential of this nucleoside for the treatment of HIV- and HBV-infected individuals.