title: In vitro and in vivo pharmacokinetic features and metabolism of the novel cytotoxic nucleoside analog 3'-azidothymidine 5'-[p-methoxyphenyl methoxyalaninyl phosphate] (Compound 003).
abstract: The pharmacokinetic features and metabolism of the novel cytotoxic nucleoside analog Compound 003 (3'-azidothymidine 5'-[p-methoxyphenyl methoxyalaninyl phosphate], CAS 149560-32-7) were studied in both human cancer cells and mice. In mice, Compound 003 was rapidly converted into ala-AZT-MP (CAS 209214-06-2) and zidovudine (azidothymidine, AZT, CAS 30516-87-1). Maximum ala-AZT-MP concentrations were reached almost immediately (tmax < 5 min), while 50.4 min and 143.5 min were required to reach maximum AZT concentrations after intravenous and oral administration, respectively. The results indicate that paraoxon-sensitive carboxylesterases play an important role in the conversion of Compound 003 to ala-AZT-MP. This study provides the basis for future preclinical as well as clinical pharmacodynamic studies of Compound 003.
authors.affiliation: Drug Discovery Program, Parker Hughes Institute, St. Paul, Minnesota 55113, USA. fatih_uckun@ih.org
authors.forename: Fatih M
authors.initials: FM
authors.lastname: Uckun
authors.forename: Chun-Lin
authors.initials: CL
authors.lastname: Chen
authors.forename: Xing-Ping
authors.initials: XP
authors.lastname: Liu
authors.forename: Ilker
authors.initials: I
authors.lastname: Dibirdik
authors.forename: Taracad K
authors.initials: TK
authors.lastname: Venkatachalam
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics*; D001826:Body Fluids / Q000378:metabolism; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D002855:Chromatography, Thin Layer; D054306:Dideoxynucleotides; D004305:Dose-Response Relationship, Drug; D004950:Esterases / Q000037:antagonists & inhibitors; D005260:Female; D005753:Gastric Mucosa / Q000378:metabolism; D007275:Injections, Intravenous; D007413:Intestinal Mucosa / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D051379:Mice; D010261:Paraoxon / Q000494:pharmacology; D010865:Pilot Projects; D013056:Spectrophotometry, Ultraviolet; D013347:Subcellular Fractions / Q000378:metabolism; D015215:Zidovudine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics*
chemical_list: C495110:3'-azidothymidine 5'-(p-methoxyphenyl methoxyalaninyl phosphate); D000970:Antineoplastic Agents; D054306:Dideoxynucleotides; D015215:Zidovudine; D004950:Esterases; D010261:Paraoxon