Liu Xing-Jie, Lu Hua, Sun Ju-Xiang, Wang Su-Rong, Mo Yan-Shuai, Yang Xing-Sheng, Shi Ben-Kang
Qilu Hospital of Shandong University, Jinan, Shandong, China.
Linyi People's Hospital, Linyi, Shandong, China.
Eur J Drug Metab Pharmacokinet. 2016 Aug;41(4):465-8. doi: 10.1007/s13318-015-0252-y. Epub 2015 Mar 4.
Metabolism-mediated drug adverse effects (e.g., drug-drug interaction, bioactivation, etc.) strongly limit the utilization of clinical drugs. The present study aims to predict the metabolic capability of cytochrome P450 (CYP) 3A4 toward pazopanib which is an excellent drug exhibiting therapeutic role toward various cancers especially for ovarian cancer. Pazopanib can be well docked into the activity cavity of CYP3A4, and the interaction structure in pazopanib was methyl group located besides nitrogen in the five-membered ring. The distance between the hydrogen atom in methyl group and active center is 3.64 Å. The interaction amino acid is Glu374. Furthermore, both pazopanib and ketoconazole were docked into the activity cavity of CYP3A4 to compare their binding potential. The distance between ketoconazole and activity center (2.10 Å) is closer than the distance between pazopanib and activity center of CYP3A4, indicating the easy influence of CYP3A4 inhibitor toward the metabolism of pazopanib. All these data were helpful for the clinical application of pazopanib, and R&D of other tinib drug candidates as new anti-tumor drugs.
代谢介导的药物不良反应（如药物相互作用、生物活化等）严重限制了临床药物的应用。本研究旨在预测细胞色素P450（CYP）3A4对帕唑帕尼的代谢能力，帕唑帕尼是一种对多种癌症尤其是卵巢癌具有治疗作用的优秀药物。帕唑帕尼能够很好地对接至CYP3A4的活性腔中，其在帕唑帕尼中的相互作用结构是五元环中氮旁边的甲基。甲基中的氢原子与活性中心的距离为3.64 Å。相互作用的氨基酸是Glu374。此外，将帕唑帕尼和酮康唑都对接至CYP3A4的活性腔中以比较它们的结合潜力。酮康唑与活性中心的距离（2.10 Å）比帕唑帕尼与CYP3A4活性中心的距离更近，表明CYP3A4抑制剂对帕唑帕尼代谢的影响较大。所有这些数据有助于帕唑帕尼的临床应用以及其他替尼类候选药物作为新型抗肿瘤药物的研发。
