Short communication 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 ability to inhibit this cytochrome CYP2D6-dependent activity. Competitive in- hibition indicates that the drug binds the enzyme and is potentially subjected to a polymorphic metabolism. Among the 13 anticancer drugs tested, 4 compounds caused competitive inhibiton of dextromethorphan-O- demethylation: lomustine (Ki = 7.7 gM), doxorubicin (Ki = 75 ~tM), vinorelbine (Ki = 22 ~tM), and vinblastine (Ki = 42 ~tM). The results of these studies indicate that the metabolism of the drugs concerned is possibly altered in poor metabolizers of debrisoquine and requires further in- vestigation to study their specific routes of biotransforma- tion. The metabolism of these drugs probably involves various biotransformation pathways, among which the CYP2D6-dependent route would be of minor importance. A second hypothesis is that these drugs could be inhibitors of the isozyme without being a substrate.