ROLE OF CYTOCHROME-P450 ISOFORMS IN THE METABOLISM OF ABAMECTIN AND IVERMECTIN IN RATS

Abamectin (AVM) and ivermectin (IVM) are each metabolized by rat liver microsomes to 3 ''-O-desmethyl(3 ''-ODMe), 24-hydroxymethyl (24-OHMe) , and 26-hydroxymethyl (26-OHMe) derivatives. Microsomes from rats pre treated with dexamethasone(Dex), but not 3-methylcholanthrene (3MC), i ncreased the formation of 3 ''-ODMe metabolites of both AVM and IVM. T roleandomycin inhibited formation of 3 ''-ODMe metabolites by >80% by microsomes from Dex-induced rats. Therefore, cytochrome P450 3A plays a major role in this metabolic pathway. Formation of the 26-OHMe metab olites was markedly increased by microsomes from SMC-treated but not D ex-treated rats. Formation of 24-OHMe from AVM, but not IVM, was sligh tly increased by microsomes from 3MC-treated rats. Consistent with thi s observation, anti-rat cytochrome P450 1Al inhibited formation of 26- OHMe metabolites of AVM and IVM by 90 and 40%, respectively. This anti body also inhibited formation of the 24-OHMe metabolite from AVM by 60 % but not from IVM. Thus, cytochrome P450 1A1 is involved in the hydro xylation of the 26-methyl group of both AVM and IVM as well as the 24- methyl group of AVM but not the 24-methyl group of IVM.