In vivo pharmacokinetics and metabolism of anti-human immunodeficiency virus agent D4T-5 '-[P-bromophenyl methoxyalaninyl phosphate] (sampidine) in mice

d4T-5'-[p-Sampidine, bromophenyl methoxyalaninyl phosphate] (HI-113), a nov el aryl phosphate derivative of stavudine (d4T), exhibits substantially mor e potent anti-human immunodeficiency virus activity than d4T, The purpose o f the present study was to investigate the in vivo pharmacokinetics and met abolism of this promising new anti-HIV agent in mice. Here, we report that HI-113 forms two active metabolites with favorable pharmacokinetics after s ystemic administration. Plasma HI-113 concentrations were measured by analy tical high-performance liquid chromatography and the pharmacokinetic parame ters were estimated using the WinNonlin program, After intravenous administ ration, the elimination half-life (t(1/2)) of HI-113 was 3.6 min with a sys temic clearance of 174.5 ml/min/kg, HI-113 was converted to the active meta bolites alaninyl-d4T-monophosphate (ala-d4T-MP) and d4T. The T-max values f or 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 metabo lized to form d4T (T-max = 5.0 min). The elimination half-life of d4T deriv ed from intravenously administered ala-d4T-MP (32.4 min) was similar to the elimination half-life of intravenously administered d4T (26.6 min). In con trast, the elimination half-life of d4T derived from HI-113 was substantial ly longer (116.2 min). Similarly, the elimination half-life of ala-d4T-MP d erived from HI-113 (138.8 min) was markedly longer than the elimination hal f-life of ala-d4T-MP given intravenously (38.9 min). Following oral adminis tration of HI-113, the elimination half-lives of ala-d4T-MP (56.1 min) and d4T (102.6 min) were also prolonged.