Effect of cyclosporine and tacrolimus on cytochrome P450 activities in human liver microsomes
Effect of cyclosporine and tacrolimus on cytochrome P450 activities in human liver microsomes
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DOI：
10.1248/yakushi.127.209
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发表时间：
2007-01-01
影响因子：
0.3
通讯作者：
Takagi, Akira
中科院分区：
文献类型：
--
作者：
Niwa, Toshiro;Yamamoto, Sachiko;Takagi, Akira
比较了环孢素和他克莫司对细胞色素P450(CYP)1A2介导的细胞色素P450 O-脱乙基化、细胞色素P2C9介导的甲苯丁胺羟化、细胞色素P2C19介导的S-美苯妥因4‘-羟化、细胞色素P2D6介导的去氢异喹4-羟化、细胞色素P2E1A1介导的氯唑沙宗6-羟基化、细胞色素P3A4介导的硝苯地平氧化和细胞色素P3A4介导的睾酮6β-羟基化活性的影响。环孢素和他克莫司在0.2或2 mM的浓度下既不抑制也不刺激除细胞色素P3A4外的任何代谢活性。另一方面，环孢素和他克莫司竞争性抑制细胞色素P3A4介导的硝苯地平氧化活性，抑制常数(K-I)分别为1.42和0.36 pM。此外，20MU M环孢素对细胞色素P450 2C19和细胞色素P450 2D6的抑制作用分别为29%和30%。这些结果表明，他克莫司不会通过抑制肝脏代谢而与其他药物发生显著的相互作用。环孢素具有药代动力学抑制作用的原因可能是其代谢酶的剂量和/或游离浓度高于他克莫司，而不是抑制电位的差异。未观察到明显的底物依赖性对细胞色素P3A4抑制电位的影响。
The effects of cyclosporine and tacrolimus on cytochrome P450 (CYP) 1A2-mediated 7-ethoxyresorufin O-deethylation, CYP2C9-mediated tolbutamide hydroxylation, CYP2C19-mediated S-mephenytoin 4'-hydroxylation, CYP2D6-mediated debrisoquine 4-hydroxylation, CYP2E1-mediated chlorzoxazone 6-hydroxylation, CYP3A4-mediated nifedipine oxidation, and CYP3A4-mediated testosterone 6 beta-hydroxylation activities in human liver microsomes were compared. Cyclosporine and tacrolimus, at concentrations of 0.2 or 2 mu m, neither inhibited nor stimulated any of the metabolic activities except for those of CYP3A4. On the other hand, cyclosporine and tacrolimus competitively inhibited CYP3A4-mediated nifedipine oxidation activity, with inhibition constants (K-i) of 1.42 and 0.36 pm, respectively. In addition, 20 mu m cyclosporine inhibited CYP2C19 and CYP2D6 activities by 29% and 30%, respectively. These results suggest that tacrolimus would not cause clinically significant interactions with other drugs, which are metabolized by CYPs, via the inhibition of hepatic metabolism and that the reason why cyclosporine, but not tacrolimus, has a pharmacokinetic inhibitory effect might be that the dosage and/or the unbound concentrations around its metabolic enzymes are higher than those of tacrolimus, rather than the differences in the inhibition potential. Obvious substrate-dependent effects on CYP3A4-inhibition potential were not observed.