Abstract

d4T-5′-[p-Sampidine, bromophenyl methoxyalaninyl phosphate] (HI-113), a novel aryl phosphate derivative of stavudine (d4T), exhibits substantially more potent anti-human immunodeficiency virus activity than d4T. The purpose of the present study was to investigate the in vivo pharmacokinetics and metabolism of this promising new anti-HIV agent in mice. Here, we report that HI-113 forms two active metabolites with favorable pharmacokinetics after systemic administration. Plasma HI-113 concentrations were measured by analytical high-performance liquid chromatography and the pharmacokinetic parameters were estimated using the WinNonlin program. After intravenous administration, the elimination half-life (t_1/2) of HI-113 was 3.6 min with a systemic clearance of 174.5 ml/min/kg. HI-113 was converted to the active metabolites alaninyl-d4T-monophosphate (ala-d4T-MP) and d4T. TheT_max values for ala-d4T-MP and d4T derived from intravenously administered HI-113 were 5.1 and 17.4 min, respectively. The elimination half-life for synthetic ala-d4T-MP was 38.9 min after intravenous administration. Ala-d4T-MP was metabolized to form d4T (T_max = 5.0 min). The elimination half-life of d4T derived from intravenously administered ala-d4T-MP (32.4 min) was similar to the elimination half-life of intravenously administered d4T (26.6 min). In contrast, the elimination half-life of d4T derived from HI-113 was substantially longer (116.2 min). Similarly, the elimination half-life of ala-d4T-MP derived from HI-113 (138.8 min) was markedly longer than the elimination half-life of ala-d4T-MP given intravenously (38.9 min). Following oral administration of HI-113, the elimination half-lives of ala-d4T-MP (56.1 min) and d4T (102.6 min) were also prolonged.