In vitro and in vivo metabolism and pharmacokinetics of bis [(T-butyl)-S-acyl-2-thioethyl]-beta-1-2 ',3 '-dideoxy-5-fluorocytidine monophosphate

Exposure to 10 &M L-FddCMP-bisSATE led to formation of intracellular L-FddC TP levels of 410.1 +/- 46.2 and 242.1 +/- 13.2 pmol/10(6) cells in unstimul ated and PHAstimulated PBM cells, respectively; whereas, exposure of cells to the parent nucleoside, L-FddC, generated 5 - 10-fold less L-FddCTP. In H ep-G2 cells and EGF/HGF stimulated and unstimulated primary cultured hepato cytes, 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-FddC MPSH, and M I, were detected intracellularly and extracellularly in all cel l 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 o ral administration of an equivalent dose, the absolute oral bioavailability of L-FddC derived from L-FddCMP-bisSATE administration was 65%.