HUMAN LIVER MICROSOMAL METABOLISM OF PACLITAXEL AND DRUG-INTERACTIONS

The aim of this study was to investigate the influence of several anti cancer drugs and investigational multidrug resistance (MDR) reversing agents on the hepatic metabolism of paclitaxel (Taxol) to its primary metabolites, 6 alpha-hydroxypaclitaxel (metabolite, M-A) and 3'-p-hydr oxypaclitaxel (metabolite, M-B). There is significant inter-individual variability associated with the levels of these two metabolites. In m any cases, 6 alpha-hydroxypaclitaxel has been observed to be the predo minant metabolite, in others, 3'-p-hydroxypaclitaxel has been the prin cipal metabolite. The formation of 6a-hydroxypaclitaxel and 3'-p-hydro xypaclitaxel is catalyzed by cytochrome P450 isozymes CYP2C8 and CYP3A 4, respectively. A number of factors, including co-administration of d rugs and adjuvants, are known to influence the activity of these isozy mes. Therefore, the influence of MDR reversing agents, R-verapamil, cy closporin A (CsA) and tamoxifen and anti-cancer drugs doxorubicin, eto poside (VP-16) and cisplatin on paclitaxel metabolism was assessed emp loying human liver microsomes in vitro. Paclitaxel (10 mu M) was incub ated with human liver microsomes (1 mg protein, -0.34 nmol CYP) in the presence of a NADPH generating system at 37 degrees C for 1 h, with a nd without the: presence of interacting drug. Controls included incuba tions with quercetin and ketoconazole, known inhibitors of 6 alpha-hyd roxypaclitaxel and 3'-p-hydroxypaclitaxel formation, respectively. At the end of the incubation period, paclitaxel and the metabolites were extracted in ethyl acetate and analyzed employing an HPLC method. Sign ificant inhibition of paclitaxel conversion to 6 alpha-hydroxypaclitax el and 3'-p-hydroxypaclitaxel was observed in the presence of R-verapa mil, tamoxifen and VP-16 (P 0.005). Doxorubicin significantly inhibite d the formation of 3'-p-hydroxypaclitaxel and CsA inhibited the format ion of 6 alpha-hydroxypaclitaxel (P 0.005). This study demonstrates th at co-administration of several of the above listed compounds could le ad to significant changes in the pharmacokinetics of paclitaxel.