THE ROLE OF HUMAN CYTOCHROME-P450 ENZYMES IN THE METABOLISM OF ANTICANCER AGENTS - IMPLICATIONS FOR DRUG-INTERACTIONS

1 Little information is available about the pharmacokinetic interactio ns of anticancer drugs in man. However, clinically significant drug in teractions do occur in cancer chemotherapy, and it is likely that impo rtant interactions have not been recognized. 2 Specific cytochrome P45 0 (CYP) enzymes have been recently shown to be involved in the metabol ism of several essential anticancer agents. In particular, enzymes of the CYP3A subfamily play a role in the metabolism of many anticancer d rugs, including epipodophyllotoxins, ifosphamide, tamoxifen, taxol and vinca alkaloids. CYP3A4 has been shown to catalyse the activation of the prodrug ifosphamide, raising the possibility that ifosphamide coul d be activated in tumour tissues containing this enzyme. 3 As examples of recently found, clinically significant interactions, cyclosporin c onsiderably increases plasma doxorubicin and etoposide concentrations. Although cyclosporin and calcium channel blockers may influence the p harmacokinetics of certain anticancer agents by inhibiting their CYP3A mediated metabolism, it is more likely that these P-glycoprotein inhi bitors inhibit P-glycoprotein mediated drug elimination. 4 Appropriate caution should be exercised when combining P-glycoprotein inhibitors and potential CYP3A inhibitors with cancer chemotherapy.