Drug interaction of thalidomide with midazolam and other compounds : heterotropic cooperativiy of human cyochrome P450

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。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。沙利度胺可能通过多态性P450 3A 5的异向性协同作用发生药物相互作用。采用了一种新的肝细胞系系统，其中分化的HepaRG冷冻保存（Biopredic International，Rennes，France）。这些结果表明，培养的人细胞系系统与分化的HepaRG冻存可适用于沙利度胺药物相互作用的研究。正在使用模拟体内人类肝脏的新HepaRG细胞系统研究5-羟沙利度胺进一步氧化代谢为5-羟基沙利度胺GSH-缀合物的形成。

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. 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.We investigate these drug interactions in cultured human liver cell line system more closely resembled livers. A new hepatic cell line system with differentiated HepaRG cryopreserved(Biopredic International, Rennes, France) was adopted. These results suggest that cultured human cell line system with differentiated HepaRG cryopreserved could be applicable to thalidomide drug interaction study. Further oxidative metabolism of 5-hydoroxythalidomide to 5-hydroxythalidomide GSH-conjugate formation is under investigation using the new HepaRG cell system mimicking in vivo human livers.