P450 interaction with farnesyl-protein transferase inhibitors - Metabolic stability, inhibitory potency, and P450 binding spectra in human liver microsomes
P450 interaction with farnesyl-protein transferase inhibitors - Metabolic stability, inhibitory potency, and P450 binding spectra in human liver microsomes
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DOI：
10.1016/s0006-2952(01)00724-9
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发表时间：
2001-09-15
影响因子：
5.8
通讯作者：
Lin, JH
中科院分区：
文献类型：
--
作者：
Chiba, M;Tang, CY;Lin, JH
咪唑环 2 位的甲基取代极大地改善了用于药物开发的 ras 法呢基蛋白转移酶抑制剂 (FTI) 候选药物在人肝微粒体中的药物代谢特征。甲基取代显着降低了未取代的 FTI 对 CYP3A4（12-403 倍）和 2C9（4.2-28 倍）的 P450 抑制效力，而对 CYP2D6 酶几乎没有影响。免疫化学抑制研究表明，CYP3A4 在未取代和 2-甲基取代的含咪唑 FTI 候选物的代谢中发挥着主导作用。所有未取代的 FTI 均观察到与人肝微粒体的 H 型结合光谱非常强，而甲基取代显着削弱了 II 型光谱或将光谱类型从 II 转变为 I。这表明咪唑部分上的甲基取代干扰了底物 - P450 血红素相互作用，可能是由于甲基引起的空间效应。动力学研究表明，甲基取代以相同程度增加了 V-max 和 K-m 值。这些研究表明，咪唑环上的 2-甲基取代通过降低抑制 CYP3A4 介导的代谢的潜力而不影响内在代谢清除率 (V-max/K-m) 来改善其药物代谢特征。 (C) 2001 Elsevier Science Inc. 保留所有权利。
Methyl substitution at the 2-position of the imidazole ring greatly improved drug metabolism profiles, in human liver microsomes, of ras famesyl-protein transferase inhibitor (FTI) candidates for drug development. Methyl substitution markedly reduced the P450 inhibitory potency of non-substituted FTIs for CYP3A4 (by a factor of 12-403) and 2C9 (by a factor of 4.2-28), while it had little effect on the CYP2D6 enzyme. An immunochemical inhibition study demonstrated that CYP3A4 plays a predominant role in the metabolism of both nonsubstituted and 2-methyl-substituted imidazole-containing FTI candidates. Very strong type H binding spectra with human liver microsomes were observed for all non-substituted FTIs, while methyl substitution markedly weakened type II spectra or shifted the type of spectra from II to I. This indicated that methyl substitution on the imidazole moiety interfered with the substrate-P450 heme interaction, likely due to a steric effect caused by the methyl group. A kinetics study revealed that the methyl substitution increased V-max and K-m values to the same extent. These studies suggested that the 2-methyl substitution on the imidazole ring improved its drug metabolism profile by reducing the potential to inhibit CYP3A4-mediated metabolism without affecting intrinsic metabolic clearance (V-max/K-m). (C) 2001 Elsevier Science Inc. All rights reserved.