title: In vivo pharmacokinetics and metabolism of anti-human immunodeficiency virus agent D4T-5'-[p-bromophenyl methoxyalaninyl phosphate] (SAMPIDINE) in mice.
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. The T(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.
authors.affiliation: Drug Discovery Program, Parker Hughes Institute, St. Paul, Minnesota 55113, USA.
authors.forename: C L
authors.initials: CL
authors.lastname: Chen
authors.forename: T K
authors.initials: TK
authors.lastname: Venkatachalam
authors.forename: Z H
authors.initials: ZH
authors.lastname: Zhu
authors.forename: F M
authors.initials: FM
authors.lastname: Uckun
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D003843:Deoxycytidine Monophosphate / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000378:metabolism / Q000493:pharmacokinetics*; D054306:Dideoxynucleotides; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D013873:Thionucleotides / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*
chemical_list: D019380:Anti-HIV Agents; C117033:D4T-5'-(p-bromophenyl methoxyalaninyl phosphate); D054306:Dideoxynucleotides; D013873:Thionucleotides; D003843:Deoxycytidine Monophosphate