NDLI: 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.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Tang, Cuyue Carr, Brian A. Poignant, Frédéric Ma, Bennett Polsky-Fisher, Stacey L. Kuo, Yuhsin Strong-Basalyga, Kristie Norcross, Alisha Richards, Karen Eisenhandler, Roy Carlini, Edward J. Di Marco, Christina Ng Kuduk, Scott D. Yu, Nathan X. Raab, Conrad E. Rushmore, Tom Frederick, Clay B. Bock, Mark G. Prueksaritanont, Thomayant
Description	Country affiliation: United States Author Affiliation: Tang C ( Department of Drug Metabolism and Pharmacokinetics, Merck Research Laboratories, WP75A-203, Merck and Co., Inc., West Point, PA 19486, USA. cuyue_tang@merck.com)
Abstract	After oral treatment (once daily) for 4 weeks with the potent bradykinin B(1) 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 > or = 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.
File Format	HTM / HTML
ISSN	00223565
Issue Number	3
Volume Number	325
e-ISSN	15210103
Journal	Journal of Pharmacology and Experimental Therapeutics
Language	English
Publisher	American Society for Pharmacology and Experimental Therapeutics
Publisher Date	2008-06-01
Publisher Place	United States
Access Restriction	Subscribed
Subject Keyword	Bradykinin B1 Receptor Antagonists Humans Male Recombinant Proteins Discipline Pharmacology Blood Journal Article Receptor, Bradykinin B1 Genetics Female Acetamides Urine Macaca Mulatta Benzoates Cells, Cultured Metabolism Cytochrome P-450 Enzyme System Receptors, Steroid Animals Hepatocytes Discipline Therapeutics Cell Line, Tumor Pharmacokinetics Microsomes, Liver Bile
Content Type	Text
Resource Type	Article
Subject	Molecular Medicine Pharmacology

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