Drug Interactions of Thalidomide with Midazolam and Cyclosporine A: Heterotropic Cooperativity of Human Cytochrome P450 3A5
Drug Interactions of Thalidomide with Midazolam and Cyclosporine A: Heterotropic Cooperativity of Human Cytochrome P450 3A5
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DOI：
10.1124/dmd.108.024679
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发表时间：
2009-01-01
影响因子：
3.9
通讯作者：
Yamazaki, Hiroshi
中科院分区：
文献类型：
--
作者：
Okada, Yusuke;Murayama, Norie;Yamazaki, Hiroshi
尽管具有致畸性，但由于其免疫调节和抗血管生成的特性，沙利度胺的临床应用越来越受到关注。然而，关于沙利度胺对药物代谢酶的确切作用的报道很少。我们研究了沙利度胺对人肝微粒体细胞色素P450（P450）酶的影响，以阐明可能的药物相互作用的可能性。沙利度胺抑制重组P450 2C 19和人肝微粒体的S-美芬妥英4 '-羟基化活性：对于P450 2C 19，产生50%抑制的沙利度胺的表观浓度约为270 μ M。沙利度胺抑制咪达唑仑4-羟基化活性，但1 '-羟基化活性和总咪达唑仑氧化活性以及睾酮6 β-羟基化活性在沙利度胺存在下增强。发现重组P450 3A 5在临床相关浓度的沙利度胺（10-30 μ M）下具有改变的动力学。P450 3A 4也受到影响，但仅在较高的沙利度胺浓度。在携带CYP 3A 5 *1等位基因的肝微粒体样本中也观察到沙利度胺对咪达唑仑羟基化的增强。在存在沙利度胺的情况下，在P450 3A 5和表达P450 3A 5的肝微粒体中观察到环孢霉素A清除率的类似增加。沙利度胺的拟定效应常数大致对应于其临床血浆水平。对接研究与P450 3A 5同源性模型的基础上公布的结构的P450 3A 4，显示沙利度胺和血红素的P450 3A 5之间的密切相互作用。目前的结果表明，总咪达唑仑代谢或环孢素A清除率可能增加沙利度胺的剂量依赖性方式。涉及沙利度胺的意外药物相互作用可能通过多态性P450 3A 5的异向性协同作用发生。
There is growing clinical interest of thalidomide because of its immunomodulatory and antiangiogenic properties, despite its teratogenicity. However, little information about thalidomide has been reported regarding its precise effects on drug-metabolizing enzymes. We investigated the effects of thalidomide on cytochrome P450 (P450) enzymes in human liver microsomes to clarify the potential for possible drug interactions. Thalidomide inhibited S-mephenytoin 4'-hydroxylation activities of recombinant P450 2C19 and human liver microsomes: the apparent concentration of thalidomide producing 50% inhibition was approximately 270 mu M for P450 2C19. Midazolam 4-hydroxylation activities were suppressed by thalidomide, but activities of 1'-hydroxylation and total midazolam oxidation and testosterone 6 beta-hydroxylation were enhanced in the presence of thalidomide. Recombinant P450 3A5 was found to have altered kinetics at clinically relevant concentrations of thalidomide (10-30 mu M). P450 3A4 was also affected, but only at higher thalidomide concentrations. Enhanced midazolam hydroxylation by thalidomide was also seen in liver microsomal samples harboring the CYP3A5*1 allele. Similarly enhanced rates of cyclosporine A clearance were observed in P450 3A5 and liver microsomes expressing P450 3A5 in the presence of thalidomide. A proposed effector constant for thalidomide corresponded roughly to its clinical plasma levels. Docking studies with a P450 3A5 homology model, based on the published structure of P450 3A4, revealed close interaction between thalidomide and the heme of P450 3A5. The present results suggest that total midazolam metabolism or cyclosporine A clearance may be increased by thalidomide in a dose-dependent manner. Unexpected drug interactions involving thalidomide might occur via heterotropic cooperativity of polymorphic P450 3A5.