title: In vitro and in vivo metabolism and pharmacokinetics of bis [(t-butyl)-S-acyl-2-thioethyl]-beta-L-2',3'-dideoxy-5-fluorocytidine monophosphate.
abstract: Exposure to 10 &M L-FddCMP-bisSATE led to formation of intracellular L-FddCTP levels of 410.1(+/-) +/- 46.2 and 242.1 +/- 13.2 pmol/10(6) cells in unstimulated and PHAstimulated PBM cells, respectively; whereas, exposure of cells to the parent nucleoside, L-FddC, generated 5-10-fold less L-FddCTP. In Hep-G2 cells and EGF/HGF stimulated and unstimulated primary cultured hepatocytes, the active metabolite reached 113 +/- 29, 23.9 +/- 15.6, and 20.6 +/- 10.5 pmol/10(6) cells. Three other metabolites, L-FddCMP-monoSATE, L-FddCMP-SH, and M I, were detected intracellularly and extracellularly in all cell types examined. Intravenous administered dose of 3 mg/kg L-FddCMP-bisSATE to rhesus monkeys resulted in plasma concentration levels of 2.06 +/- 1.00 and 0.39 +/- 0.15 &M of L-FddCMP-monoSATE and L-FddC, respectively, while the prodrug was completely cleared metabolically within 15 min. Following oral administration of an equivalent dose, the absolute oral bioavailability of L-FddC derived from L-FddCMP-bisSATE administration was 65%.
authors.affiliation: Department of Clinical Pharmacology, University of Alabama at Birmingham, USA.
authors.forename: L T
authors.initials: LT
authors.lastname: Martin
authors.forename: E
authors.initials: E
authors.lastname: Cretton-Scott
authors.forename: L
authors.initials: L
authors.lastname: Placidi
authors.forename: A
authors.initials: A
authors.lastname: Faraj
authors.forename: A G
authors.initials: AG
authors.lastname: Loi
authors.forename: R F
authors.initials: RF
authors.lastname: Schinazi
authors.forename: H M
authors.initials: HM
authors.lastname: McClure
authors.forename: G
authors.initials: G
authors.lastname: Gosselin
authors.forename: J L
authors.initials: JL
authors.lastname: Imbach
authors.forename: J P
authors.initials: JP
authors.lastname: Sommadossi
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000652:urine; D001682:Biological Availability; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology / Q000652:urine; D004355:Drug Stability; D005260:Female; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008099:Liver / Q000166:cytology; D008253:Macaca mulatta; D010766:Phosphorylation
chemical_list: D000998:Antiviral Agents; C411258:FddCMP-bisSate; D003841:Deoxycytidine