Biotransformation and pharmacokinetics of prodrug 9-(β-d-1,3-dioxolan-4-yl)-2-aminopurine and its antiviral metabolite 9-(β-d-1,3-dioxolan-4-yl)guanine in mice

Abstract 9-( β - d -1,3-Dioxolan-4-yl)guanine (DXG) exhibits potent antiviral activity against human immunodeficiency virus type 1 (HIV-1) and hepatitis B virus (HBV) in vitro. However, since DXG possesses limited aqueous solubility, a more water soluble prodrug of DXG, 9-( β - d -1,3-dioxolan-4-yl)-2-aminopurine (APD), was synthesized. The purpose of this study was to characterize the pharmacokinetics of APD and its antiviral metabolite DXG in mice. Female NIH-Swiss mice were administered 100 mg/kg APD intravenously or orally. Serum, brain and liver were collected at selected times following prodrug administration and concentrations of APD and DXG were determined by HPLC. APD was efficiently converted to parent nucleoside DXG following both intravenous and oral administration. Biotransformation of APD to DXG likely occurs in the liver and is mediated by xanthine oxidase. Similar pharmacokinetic profiles for DXG were observed following either route of administration in serum, liver and brain. These results demonstrate that APD appears to be a promising prodrug for the delivery of DXG.