INHIBITORY EFFECTS OF ANTICANCER DRUGS ON DEXTROMETHORPHAN-O-DEMETHYLASE ACTIVITY IN HUMAN LIVER-MICROSOMES

The dextromethorphan-O-demethylase activity determined in human liver microsomes was used to screen various anticancer drugs for their abili ty to inhibit this cytochrome CYP2D6-dependent activity. Competitive i nhibition indicates that the drug binds the enzyme and is potentially subjected to a polymorphic metabolism. Among the 13 anticancer drugs t ested, 4 compounds caused competitive inhibiton of dextromethorphan-O- demethylation: lomustine (Ki = 7.7 muM, doxorubicin (Ki = 75 muM), vin orelbine (Ki = 22 muM), and vinblastine (Ki = 42 muM). The results of these studies indicate that the metabolism of the drugs concerned is p ossibly altered in poor metabolizers of debrisoquine and requires furt her investigation to study their specific routes of biotransformation. The metabolism of these drugs probably involves various biotransforma tion pathways, among which the CYP2D6-dependent route would be of mino r importance. A second hypothesis is that these drugs could be inhibit ors of the isozyme without being a substrate.