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METABOLISM, TRANSPORT, AND PHARMACOGENOMICS

CYP2C75-Involved Autoinduction of Metabolism in Rhesus Monkeys of Methyl 3-Chloro-3'-fluoro-4'-{(1R)-1-[({1-[(trifluoroacetyl)amino]cyclopropyl}carbonyl)amino]ethyl}-1,1'-biphenyl-2-carboxylate (MK-0686), a Bradykinin B₁ Receptor Antagonist

Departments of Drug Metabolism and Pharmacokinetics (C.T., B.A.C., B.M., S.L.P.-F., Y.K., K.S.-B., A.N., K.R., R.E., E.J.C., N.X.Y., C.E.R., T.R., T.P.), Medicinal Chemistry (C.N.D.M., S.D.K., M.G.B.), and Safety Assessment (C.B.F.), Merck Research Laboratories, West Point, Pennsylvania; and Laboratories Merck Sharp & Dohme-Chibret, Merck Research Laboratories, Clermont-Ferrand, France (F.P.)

After oral treatment (once daily) for 4 weeks with the potent bradykinin B₁ receptor antagonist methyl 3-chloro-3'-fluoro-4'-{(1R)-1-[({1-[(trifluoroacetyl)amino]cyclopropyl}carbonyl)-amino]ethyl}-1,1'-biphenyl-2-carboxylate (MK-0686), rhesus monkeys (Macaca mulatta) exhibited significantly reduced systemic exposure of the compound in a dose-dependent manner, suggesting an occurrence of autoinduction of MK-0686 metabolism. This possibility is supported by two observations. 1) MK-0686 was primarily eliminated via biotransformation in rhesus monkeys, with oxidation on the chlorophenyl ring as one of the major metabolic pathways. This reaction led to appreciable formation of a dihydrodiol (M11) and a hydroxyl (M13) product in rhesus liver microsomes supplemented with NADPH. 2) The formation rate of these two metabolites determined in liver microsomes from MK-0686-treated groups was 2-fold greater than the value for a control group. Studies with recombinant rhesus P450s and monoclonal antibodies against human P450 enzymes suggested that CYP2C75 played an important role in the formation of M11 and M13. The induction of this enzyme by MK-0686 was further confirmed by a concentration-dependent increase of its mRNA in rhesus hepatocytes, and, more convincingly, the enhanced CYP2C proteins and catalytic activities toward CYP2C75 probe substrates in liver microsomes from MK-0686-treated animals. Furthermore, a good correlation was observed between the rates of M11 and M13 formation and hydroxylase activities toward probe substrates determined in a panel of liver microsomal preparations from control and MK-0686-treated animals. Therefore, MK-0686, both a substrate and inducer for CYP2C75, caused autoinduction of its own metabolism in rhesus monkeys by increasing the expression of this enzyme.

Address correspondence to: Dr. Cuyue Tang, Department of Drug Metabolism and Pharmacokinetics, Merck Research Laboratories, WP75A-203, Merck and Co., Inc., West Point, PA 19486. E-mail: cuyue_tang{at}merck.com