KEY RESULTS
Thirteen different metabolites (M1-M13) were identified after incubation of ivermectin with human liver microsomes. Three (M1, M3, and M6) were the dominant metabolites found in microsomes, hepatocytes, and blood from volunteers after oral ivermectin administration. The chemical structure defined by LC-MS/MS and NMR indicated that M1 is 3″-O -demethyl ivermectin, M3 is 4-hydroxymethyl ivermectin, and M6 is 3″-O -demethyl, 4-hydroxymethyl ivermectin. Metabolic pathway evaluations with characterized cytochrome P450 enzymes showed that M1 was produced by CYP3A4 and CYP3A5, and that M3 and M6 were produced by CYP3A4.