Kato Yuka, Mukai Yuji, Rane Anders, Inotsume Nobuo, Toda Takaki
a Division of Clinical Pharmacology, Hokkaido Pharmaceutical University School of Pharmacy , Sapporo , Japan and.
b Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska University Hospital, Karolinska Institutet , Stockholm , Sweden.
Xenobiotica. 2018 Sep;48(9):898-903. doi: 10.1080/00498254.2017.1384079. Epub 2017 Oct 13.
1. Epoxyeicosatrienoic acids (EETs), metabolites of arachidonic acid (AA) via cytochrome P450s, have a protective effect on the cardiovascular system involving vasodilation. We have previously demonstrated that telmisartan (TEL) inhibits EETs production from AA in vitro. 2. The objectives of the study were to examine the inhibitory effect of fluvastatin (FLU), an inhibitor of CYP2C9, and the combined effect of TEL and FLU on the production of EETs using human liver microsomes. The combined effect of TEL and FLU was evaluated using two methods, the fixed concentration method and the fixed ratio method. 3. FLU significantly reduced total eicosanoids (sum of EETs and their subsequent metabolites dihydroxyeicosatrienoic acids) production at > 0.25 µM. The results of the fixed concentration method indicated that the addition of the other inhibitor resulted in significant reduction of the production of total eicosanoids in a concentration-dependent manner. In the fixed ratio method, the combination of TEL and FLU over all concentration ratios tested did not produce a horizontal shift in the dose response curves. 4. Our results showing an additive combined effect of TEL and FLU on AA metabolism, suggest that concomitant treatment with TEL and FLU would theoretically affect the vascular tone mediated by EETs from AA.
环氧二十碳三烯酸（EETs）是花生四烯酸（AA）经细胞色素P450代谢产生的产物，对心血管系统具有涉及血管舒张的保护作用。我们之前已证明替米沙坦（TEL）在体外可抑制AA生成EETs。
本研究的目的是使用人肝微粒体，检测CYP2C9抑制剂氟伐他汀（FLU）的抑制作用以及TEL与FLU联合使用对EETs生成的影响。采用固定浓度法和固定比例法两种方法评估TEL与FLU的联合作用。
FLU在浓度>0.25µM时可显著降低总类二十烷酸（EETs及其后续代谢产物二羟基二十碳三烯酸的总和）的生成。固定浓度法的结果表明，添加另一种抑制剂会导致总类二十烷酸的生成以浓度依赖的方式显著降低。在固定比例法中，TEL与FLU在所有测试浓度比例下的组合均未使剂量反应曲线产生水平位移。
我们的结果显示TEL与FLU对AA代谢具有相加的联合作用，这表明理论上TEL与FLU联合治疗会影响由AA生成的EETs介导的血管张力。
