Kato Yuka, Mukai Yuji, Rane Anders, Inotsume Nobuo, Toda Takaki
Division of Clinical Pharmacology, Hokkaido Pharmaceutical University School of Pharmacy.
Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska University Hospital, Karolinska Institutet.
Biol Pharm Bull. 2017;40(9):1409-1415. doi: 10.1248/bpb.b17-00174.
Epoxyeicosatorienoic acids (EETs) are generated from arachidonic acid (AA) by CYPs. EETs comprise four regioisomers (14,15-, 11,12-, 8,9-, and 5,6-EET). EETs show potent physiological effects, including vasodilation, anti-inflammation, myocardial preconditioning, and anti-platelet aggregation effects. We recently demonstrated that telmisartan, one of angiotensin II receptor blockers, inhibits AA metabolism by CYP enzymes, including CYP2C8, CYP2C9, and CYP2J2. We conducted studies of AA metabolism using recombinant CYP enzymes to estimate the inhibition constant and the type of inhibition by telmisartan of CYP2C9 and CYP2C8. The contribution ratio (CR) of each CYP enzyme was investigated using human liver microsomes. Dixon and Lineweaver-Burk plots indicated that telmisartan is a mixed inhibitor of both CYP2C9 and CYP2C8; telmisartan did not show a time-dependent inhibition toward these CYP enzymes. Based on the CRs, both CYP2C9 and CYP2C8 are the key enzymes in the metabolism of AA in the human liver. Uptake of telmisartan in the liver by organic anion transporting polypeptide (OATP) 1B3 and the non-linear metabolism in gastrointestinal tract augment the potential of the drug to inhibit the CYP enzymes in the liver.
环氧二十碳三烯酸（EETs）由细胞色素P450（CYPs）催化花生四烯酸（AA）生成。EETs包含四种区域异构体（14,15-、11,12-、8,9-和5,6-EET）。EETs具有强大的生理效应，包括血管舒张、抗炎、心肌预处理和抗血小板聚集作用。我们最近证明，血管紧张素II受体阻滞剂之一的替米沙坦可抑制包括CYP2C8、CYP2C9和CYP2J2在内的CYP酶对AA的代谢。我们使用重组CYP酶进行AA代谢研究，以评估替米沙坦对CYP2C9和CYP2C8的抑制常数和抑制类型。使用人肝微粒体研究每种CYP酶的贡献率（CR）。Dixon和Lineweaver-Burk图表明，替米沙坦是CYP2C9和CYP2C8的混合抑制剂；替米沙坦对这些CYP酶未表现出时间依赖性抑制。基于CRs，CYP2C9和CYP2C8都是人肝脏中AA代谢的关键酶。有机阴离子转运多肽（OATP）1B3介导替米沙坦在肝脏中的摄取以及胃肠道中的非线性代谢增强了该药物抑制肝脏中CYP酶的潜力。
