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SHORT COMMUNICATION

CYTOCHROME P450 2C8 (CYP2C8)-MEDIATED HYDROXYLATION OF AN ENDOTHELIN ET_A RECEPTOR ANTAGONIST IN HUMAN LIVER MICROSOMES

Department of Drug Metabolism, Merck Research Laboratories, West Point, Pennsylvania (B.M., R.S., M.L.S., C.T.); and Bristol-Myers Squibb, Princeton, New Jersey (A.D.R.)

In vitro studies were performed to identify the human cytochrome P450 enzyme(s) involved in the hydroxylation (isopropyl moiety) of a previously reported endothelin ET_A receptor antagonist, compound A [(+)-(5S,6R,7R)-2-isopropylamino-7-{4-methoxy-2-[(2R)-3-methoxy-2-methylpropyl]}-5-(3,4-methylenedioxyphenyl)cyclopenteno(1,2-b) pyridine 6-carboxylic acid]. Several lines of evidence indicated that the reaction was mainly catalyzed by CYP2C8. Of the 10 recombinant cytochrome P450 isoforms tested, only CYP2C8 exhibited hydroxylase activity. In agreement, inhibitory antibodies selective for CYP2C8 attenuated (>95%) the hydroxylase activity in human liver microsomes, whereas antibodies and chemical inhibitors selective for other cytochrome P450 isoforms had a minor or no effect on the reaction. In addition, the formation of the hydroxy metabolite correlated well with CYP2C8-selective paclitaxel 6-hydroxylation (r² 0.92; p < 0.0001) and amodiaquine N-de-ethylation (r² 0.91; p < 0.0001) in a bank of human liver microsomes (n = 15 organ donors). Finally, compound A hydroxylase activity conformed to Michaelis-Menten kinetics, and the K_m (Michaelis constant) in human liver microsomes was similar to that of CYP2C8 (10 µM). It is concluded that the hydroxylation of compound A is mainly catalyzed by CYP2C8, and thus the reaction can possibly serve as an alternative marker assay for CYP2C8 in human liver microsomes.

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