VARIABILITY IN HUMAN CYTOCHROME-P450 PACLITAXEL METABOLISM

Formation of 6 alpha-hydroxypaclitaxel has been described as the prima ry biotransformation pathway for paclitaxel in vitro and in vivo, with additional formation of two other ''minor'' metabolites. Using a larg e group (n = 49) of human liver microsomes, and P450s heterologously e xpressed in cell lines, our aims were to elucidate the P450s responsib le for and investigate variability in paclitaxel metabolite formation. Four metabolites of paclitaxel (6 alpha-hydroxypaclitaxel, metabolite s B, C and A) were formed in vitro, via CYP2C8, 3A4, 3A4 and both 2C8 and 3A4, respectively. Although 6 alpha-hydroxypaclitaxel was predomin ant in the majority of livers, metabolites B and C (formed by CYP3A4) were predominant in 11/49 and 2/49 livers, respectively. Predominance of metabolite B over 6 alpha-hydroxypaclitaxel was more likely in live r microsomes from donors known to be exposed to phenobarbital (P = .00 9), and tended to be more likely in diseased vs. normal livers (P = .0 47). Formation rates for 6 alpha-hydroxypaclitaxel, A, B, and C were l ower in diseased liver vs. normal liver (P < .001). Rates of formation of metabolites B and C were highly correlated with each other (r(2) = .91; P (.001) and with midazolam 4-hydroxylation (r(2) = .87 & 0.86, respectively; P < .001). Inhibitor experiments suggest that typical CY P3A substrates/inhibitors (e.g., cyclosporin, epipodophyllotoxins) may significantly interact with paclitaxel in vivo. In a single patient i n whom plasma samples were measured on two occasions, metabolite A (th e dihydroxylate) was predominant, and systemic clearance of paclitaxel was lower in a course administered 1 day vs. 6 wk after a course of f luconazole therapy. We report that 6 alpha-hydroxypaclitaxel, formed v ia CYP2C8, is not the predominant paclitaxel metabolite in all individ uals, and that CYP3A4 catalytic activity is important to overall pacli taxel metabolism in humans.