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

沙利度胺与咪达唑仑和其他化合物的药物相互作用：人细胞色素 P450 的异向协同作用

• 批准号: 21590177
• 负责人: MURAYAMA Norie
• 金额: $ 3万
• 依托单位: Showa Pharmaceutical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2009
• 资助国家: 日本
• 起止时间: 2009 至 2011
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-21590177/
• 关键词: 薬物相互作用; サリドマイド; 協同性; ヒト型モデルマウス; P450; HepaRG; チトクロムP450; CYP3A4; GSH; CYP3A; 促進定数; ミダゾラム水酸化活性

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.

尽管沙利度胺具有致畸作用，但由于其免疫调节和抗血管生成作用，临床上对其的兴趣与日俱增。然而，关于沙利度胺对药物代谢酶的确切影响的报道很少。我们研究了沙利度胺对人肝微粒体中细胞色素P450(P450)酶的影响，以阐明可能的药物相互作用的可能性。目前的结果提示，沙利度胺可能以剂量依赖的方式增加咪达唑仑的总代谢或环孢素A的清除量。涉及沙利度胺的意外药物相互作用可能是通过多态P450 3A5的异质性协同作用发生的。我们在更接近肝脏的培养人肝细胞系中研究了这些药物相互作用。采用一种新的分化的HepaRG冻存肝细胞系(Biopredic International，法国雷恩)。这些结果表明，经分化的HepaRG冻存培养的人细胞系可用于沙利度胺药物相互作用的研究。5-羟氧基沙利度胺的进一步氧化代谢为5-羟基沙利度胺GSH结合物的研究正在使用模拟人体肝脏的新的HepaRG细胞系统进行。

项目成果

In vivo formation of a glutathione conjugate derived from thalidomide in humanized uPA-NOG mice.

• DOI: 10.1021/tx200005g
• 发表时间: 2011-03-21
• 期刊: Chemical research in toxicology
• 影响因子: 4.1
• 作者: Yamazaki H;Suemizu H;Igaya S;Shimizu M;Shibata N;Nakamura M;Chowdhury G;Guengerich FP
• 通讯作者: Guengerich FP

An improved method to assess internal radiation exposure in humans using in vivo and in vitro animal pharmacokinetic data

使用体内和体外动物药代动力学数据评估人体内部辐射暴露的改进方法

• 发表时间: 2010
• 作者: Toshihiko Ikeda;Norie Murayama and Hiroshi Yamazaki
• 通讯作者: Norie Murayama and Hiroshi Yamazaki

Remarked properties of human cytochrome P450 1A2 and 3A5 in function and cooperativity for drug development

人细胞色素 P450 1A2 和 3A5 在药物开发中的功能和协同性的显着特性

• 发表时间: 2009
• 作者: Seki K;Senzaki K;Tsuduki Y;Ioroi T;Fujii M;Yamauchi;H;Shiraishi Y;Nakata I;Nishiguchi K;Matsubayashi T;Takakubo Y;Okamura N;Yamamori M;Tamura T;Sakaeda T;山崎浩史
• 通讯作者: 山崎浩史

Comparison of cytochrome P450 2D6 and variants in terms of drug oxidation rates and substrate inhibition.

• DOI: 10.2174/138920011795495286
• 发表时间: 2011-05
• 期刊: Current drug metabolism
• 影响因子: 2.3
• 作者: T. Niwa;N. Murayama;H. Yamazaki

Individual Differences in Pharmacokinetics and Pharmacodynamics of Anesthetic Agent Propofol with Regard to CYP2B6 and UGT1A9 Genotype and Patient Age

• DOI: 10.2133/dmpk.dmpk-11-rg-039
• 发表时间: 2011-01-01
• 期刊: DRUG METABOLISM AND PHARMACOKINETICS
• 影响因子: 2.1
• 作者: Kansaku, Fumiyasu;Kumai, Toshio;Yamazaki, Hiroshi
• 通讯作者: Yamazaki, Hiroshi