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Received for publication April 23, 2004.
Revised August 4, 2004.
Accepted for publication August 5, 2004.
The contribution of human cytochrome P450 (P450) isoforms to the metabolism of aprepitant in humans was investigated using recombinant P450s and inhibition studies. In addition, aprepitant was evaluated as an inhibitor of human P450s. Metabolism of aprepitant by microsomes prepared from baculovirus-expressed human P450s was observed only when CYP1A2, CYP2C19 or CYP3A4 were present in the expression system. Incubation with CYP1A2 and CYP2C19 yielded only products of O-dealkylation while CYP3A4 catalyzed both N- and O-dealkylation reactions. The metabolism of aprepitant by human liver microsomes was inhibited completely by ketoconazole or TAO. No inhibition was observed with other CYP isoform-selective inhibitors. Aprepitant was evaluated also as a P450 inhibitor in human liver microsomes. No significant inhibition of CYP1A2, CYP2B6, CYP2C8, CYP2D6, and CYP2E1 was observed in experiments with isoform specific substrates (IC50 > 70 µM). Aprepitant was a moderate inhibitor of CYP3A4, with Ki values of ~10 µM for the 1' and 4-hydroxylation of midazolam, and the N-demethylation of diltiazem, respectively. Aprepitant was a very weak inhibitor of CYP2C9 and CYP2C19, with Ki values of 108 and 66 µM for the 7 hydroxylation of warfarin and the 4'-hydroxylation of S-mephenytoin, respectively. Collectively, these results indicated that aprepitant is both, a substrate and a moderate inhibitor of CYP3A4.
Key words:
CYP inhibition, CYP3A, cytochrome P450, cytochrome P450 catalyzed oxidations, drug interactions
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