Taavitsainen P, Kiukaanniemi K, Pelkonen O
Department of Pharmacology and Toxicology, University of Oulu, Finland.
Eur J Clin Pharmacol. 2000 May;56(2):135-40. doi: 10.1007/s002280050731.
Metabolic interactions at the level of drug-metabolising enzymes are important for drug therapy. We investigated potential interactions of losartan, irbesartan, valsartan, eprosartan and candesartan with cytochrome P450 (CYP) enzymes in human liver microsomes.
In incubations with human liver microsomes in vitro, the inhibitory potency of angiotensin-II receptor antagonists (sartans) on CYP-specific model activities were compared by measuring the IC50 and, with respect to more potent inhibition, Ki values.
None of the five sartans inhibited CYP2A6-, CYP2D6- or CYP2E1-associated activities (coumarin 7-hydroxylation, dextromethorphan O-demethylation and chlorzoxazone 6-hydroxylation, respectively) to any significant extent. Losartan and irbesartan inhibited the CYP2C9-associated tolbutamide methylhydroxylation more potently (Ki values 4.1 microM and 24.5 microM), than valsartan, candesartan or eprosartan (Ki values 135 microM, 155 microM and > 1000 microM, respectively). Losartan and irbesartan inhibited CYP1A2- and CYP3A4-associated activities (ethoxyresorufin O-deethylation and testosterone 6beta-hydroxylation) with relatively weak affinities (IC50 values between 200 microM and 500 microM). CYP2C1OFF S-mephenytoin 4'-hydroxylation activity was inhibited by losartan (IC50 value 138 microM) and much less or not at all by the other sartans tested.
All sartans except eprosartan have at least some affinity for CYP2C9, but only losartan has an affinity for CYP2C19. Losartan and irbesartan have modest affinity for CYP1A2 and CYP3A4. This would suggest that the theoretical potential for drug interactions is likely to be quite low, with the possible exceptions of losartan and irbesartan for CYP2C9. Based on these findings, further studies on the interaction potential of losartan and irbesartan are warranted.
药物代谢酶水平的代谢相互作用对药物治疗很重要。我们研究了氯沙坦、厄贝沙坦、缬沙坦、依普罗沙坦和坎地沙坦与人肝微粒体中细胞色素P450（CYP）酶的潜在相互作用。
在体外与人肝微粒体的孵育中，通过测量IC50并针对更强效的抑制作用测量Ki值，比较血管紧张素II受体拮抗剂（沙坦类）对CYP特异性模型活性的抑制效力。
五种沙坦类药物均未对CYP2A6、CYP2D6或CYP2E1相关活性（分别为香豆素7-羟基化、右美沙芬O-去甲基化和氯唑沙宗6-羟基化）产生任何显著抑制。氯沙坦和厄贝沙坦对CYP2C9相关的甲苯磺丁脲甲基羟基化的抑制作用比缬沙坦、坎地沙坦或依普罗沙坦更强（Ki值分别为4.1微摩尔/升和24.5微摩尔/升），缬沙坦、坎地沙坦或依普罗沙坦的Ki值分别为135微摩尔/升、155微摩尔/升和>1000微摩尔/升。氯沙坦和厄贝沙坦以相对较弱的亲和力抑制CYP1A2和CYP3A4相关活性（乙氧基异吩恶唑酮O-脱乙基化和睾酮6β-羟基化）（IC50值在200微摩尔/升和500微摩尔/升之间）。氯沙坦抑制CYP2C19的S-美芬妥因4'-羟基化活性（IC50值为138微摩尔/升），而其他测试的沙坦类药物抑制作用小得多或根本没有抑制作用。
除依普罗沙坦外，所有沙坦类药物对CYP2C9至少有一定亲和力，但只有氯沙坦对CYP2C19有亲和力。氯沙坦和厄贝沙坦对CYP1A2和CYP3A4有适度亲和力。这表明药物相互作用的理论可能性可能相当低，氯沙坦和厄贝沙坦与CYP2C9相互作用可能是例外情况。基于这些发现，有必要对氯沙坦和厄贝沙坦的相互作用潜力进行进一步研究。
