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Vol. 29, Issue 7, 1035-1041, July 2001

SHORT COMMUNICATION
In Vivo Pharmacokinetics and Metabolism of Anti-Human Immunodeficiency Virus Agent d4T-5'-[p-Bromophenyl Methoxyalaninyl Phosphate] (SAMPIDINE) in Mice

Chun-Lin Chen, T. K. Venkatachalam, Zhao-Hai Zhu, and Fatih M. Uckun

Drug Discovery Program (C.-L.C., F.M.U.), Departments of Pharmaceutical Sciences (C.-L.C., F.M.U.), Chemistry (T.K.V., Z.-H.Z.), and Immunology (F.M.U.), Parker Hughes Institute, St. Paul, Minnesota

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 (t1/2) 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. The Tmax 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 (Tmax = 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.

Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics


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Copyright © 2001 by the American Society for Pharmacology and Experimental Therapeutics.