title: In vivo toxicity, pharmacokinetics, and anti-human immunodeficiency virus activity of stavudine-5'-(p-bromophenyl methoxyalaninyl phosphate) (stampidine) in mice.
abstract: We have evaluated the clinical potential of stavudine-5'-(p-bromophenyl methoxyalaninyl phosphate(stampidine [STAMP]), a novel aryl phosphate derivative of stavudine, as a new anti-human immunodeficiency virus (anti-HIV) agent, by examining its acute, subacute, and chronic toxicity profile in mice as well as by testing its antiviral activity in a surrogate human peripheral blood lymphocyte (Hu-PBL)-SCID mouse model of human AIDS. STAMP was very well tolerated in BALB/c and CD-1 mice, without any detectable acute or subacute toxicity at single intraperitoneal or oral bolus doses as high as 500 mg/kg of body weight. Notably, daily administration of STAMP intraperitoneally or orally for up to 8 consecutive weeks was not associated with any detectable toxicity at cumulative dose levels as high as 6.4 g/kg. Micromolar concentrations of the active STAMP metabolite in plasma were rapidly achieved and maintained for more than 4 h after parenteral as well as oral administration of a nontoxic 100-mg/kg bolus dose of STAMP. In accordance with its favorable pharmacokinetic profile and in vitro potency, STAMP exhibited dose-dependent and potent in vivo anti-HIV activity in Hu-PBL-SCID mice against a genotypically and phenotypically nucleoside analog reverse transcriptase inhibitor (NRTI)-resistant clinical HIV type 1 (HIV-1) isolate (BR/92/019; D67N, L214F, T215D, K219Q) at nontoxic dose levels. The remarkable in vivo safety and potency of STAMP warrants the further development of this promising new antiretroviral agent for possible clinical use in patients harboring NRTI-resistant HIV-1.
authors.affiliation: Drug Discovery Program, Departments of Virology, Immunology, Pathology, Pharmaceutical Sciences, and Chemistry, Parker Hughes Institute, St. Paul, and Parker Hughes Center for Clinical Immunology, Roseville, Minnesota 55113, USA. fatih_uckun@ih.org
authors.forename: Fatih M
authors.initials: FM
authors.lastname: Uckun
authors.forename: Sanjive
authors.initials: S
authors.lastname: Qazi
authors.forename: Sharon
authors.initials: S
authors.lastname: Pendergrass
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Lisowski
authors.forename: Barbara
authors.initials: B
authors.lastname: Waurzyniak
authors.forename: Chun-Lin
authors.initials: CL
authors.lastname: Chen
authors.forename: T K
authors.initials: TK
authors.lastname: Venkatachalam
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019380:Anti-HIV Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D054306:Dideoxynucleotides; D024882:Drug Resistance, Viral; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1; D006801:Humans; D007274:Injections, Intraperitoneal; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D018119:Stavudine / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D013938:Thymidine Monophosphate / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity
chemical_list: D019380:Anti-HIV Agents; D054306:Dideoxynucleotides; C472384:stampidine; D013938:Thymidine Monophosphate; D018119:Stavudine