EFFECTS OF ROXITHROMYCIN, ERYTHROMYCIN AND TROLEANDOMYCIN ON THEIR N-DEMETHYLATION BY RAT AND HUMAN CYTOCHROME-P450 ENZYMES

1. The effects of treatment of rat with roxithromycin, erythromycin an d troleandomycin as well as other chemicals including typical cytochro me P450 inducers were examined in rat and human liver microsomes. 2. E rythromycin and troleandomycin but not roxithromycin caused slight inc reases in CYP3A1 levels and the N-demethylation of roxithromycin, eryt hromycin and troleandomycin and oxidation of nifedipine in rat, but no ne of these chemicals induced significantly CYP2B1 levels or benzpheta mine N-demethylation activities. 3. Dexamethasone and pregnenolone 16 alpha-carbonitrile induced CYP3A1 levels and N-demethylation of roxith romycin, erythromycin and troleandomycin but not of benzphetamine, in rat liver microsomes. Treatment of rat with phenobarbital caused incre ases in both CYP2B1 and 3A1 levels and all of the N-demethylation acti vities examined. Phenytoin and metyrapone produced increases in conten ts of 2B1 and activities of benzphetamine N-demethylation as well as o f roxithromycin, erythromycin and troleandomycin, although these two i nducers did not induce 3A1 protein significantly. 4. In man, a liver s ample that was high in CYP3A4 and nifedipine oxidation activity was fo und to be the most active in N-demethylation activities towards these substrates examined. In addition, recombinant 3A4 catalysed very effic iently the N-demethylation of roxithromycin, erythromycin and troleand omycin in reconstituted monooxygenase systems. 5. These data suggest t hat erythromycin and troleandomycin, but not roxithromycin, were able to induce CYP3A1 in rat liver microsomes, and that N-demethylation of roxithromycin, erythromycin and troleandomycin were catalysed mainly b y 3A1 (and partly by 2B1) in rat and by 3A4 in man.