Z. Zeng et al., IDENTIFICATION OF CYTOCHROME P4503A4 AS THE MAJOR ENZYME RESPONSIBLE FOR THE METABOLISM OF IVERMECTIN BY HUMAN LIVER-MICROSOMES, Xenobiotica, 28(3), 1998, pp. 313-321
1. Ivermectin was extensively metabolized by human liver microsomes to
at least 10 metabolites. The structure of many of them (mostly hydrox
ylated and demethylated) was determined by H-1-NMR and LC/MS. 2. To de
termine which human cytochrome P450 isoform(s) is responsible for the
metabolism of ivermectin, chemical inhibitors including sulphaphenazol
e, quinidine, furafylline, troleandomycin (TAO) and diethyldithiocarba
mate (DDC) were used to evaluate their effect on ivermectin metabolism
. TAO, a specific inhibitor of cytochrome P4503A4, was the most potent
inhibitor, inhibiting the total metabolism as well as formation of ea
ch metabolite. Metabolism was also inhibited by an anti-human cytochro
me 3A4 antibody by 90%. 3. When ivermectin was incubated with microsom
es from cells expressing CYP1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2
E1 or 3A4 at 4 mg/ml protein concentrations, metabolic activity was on
ly detected with the microsomes containing CYP3A4. The metabolic profi
le from cDNA-expressed CYP3A4 microsomes was qualitatively similar to
that from human liver microsomes. 4. Thus, cytochrome P4503A4 is the p
redominant isoform responsible for the metabolism of ivermectin by hum
an liver microsomes.