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
Department of Drug Metabolism and Pharmacokinetics, Merck Research Laboratories, WP75A-203, Merck and Co., Inc., West Point, PA 19486, USA.
J Pharmacol Exp Ther. 2008 Jun;325(3):935-46. doi: 10.1124/jpet.107.136044. Epub 2008 Feb 29.
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.
用强效缓激肽B(1)受体拮抗剂3-氯-3'-氟-4'-{(1R)-1-[({1-[(三氟乙酰基)氨基]环丙基}羰基)-氨基]乙基}-1,1'-联苯-2-羧酸甲酯（MK-0686）对恒河猴（猕猴）进行口服治疗（每日一次）4周后，恒河猴体内该化合物的全身暴露量呈剂量依赖性显著降低，提示存在MK-0686代谢的自身诱导现象。这一可能性得到了两项观察结果的支持。1）MK-0686在恒河猴体内主要通过生物转化消除，氯苯环上的氧化是主要代谢途径之一。在补充了NADPH的恒河猴肝微粒体中，该反应导致可观的二氢二醇（M11）和羟基（M13）产物的形成。2）在MK-0686处理组的肝微粒体中测定的这两种代谢物的形成速率比对照组的值高≥2倍。对重组恒河猴P450以及抗人P450酶单克隆抗体的研究表明，CYP2C75在M11和M13的形成中起重要作用。MK-0686对该酶的诱导作用通过其在恒河猴肝细胞中mRNA的浓度依赖性增加得到进一步证实，更有说服力的是，在MK-0686处理动物的肝微粒体中，CYP2C蛋白增加，且对CYP2C75探针底物的催化活性增强。此外，在一组来自对照和MK-0686处理动物的肝微粒体制剂中，观察到M11和M13的形成速率与对探针底物的羟化酶活性之间具有良好的相关性。因此，既是CYP2C75底物又是诱导剂的MK-0686，通过增加该酶的表达，在恒河猴体内引起了自身代谢的自身诱导。
