Regulation and Prequalification, Access to Medicines and Health Products, World Health Organization, Avenue Appia 20, 1211, Geneva 27, Switzerland; Regulatory Science, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1, Tanabe-dori, Mizuho-ku, Nagoya, 467-8603, Japan.
Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aramaki-Aoba, Aoba-ku, Sendai, 980-8578, Japan; Division of Risk Assessment, National Institute of Health Sciences, Tonomachi 3-25-26, Kawasaki-ku, Kanagawa, 210-9501, Japan.
Drug Metab Pharmacokinet. 2020 Dec;35(6):485-496. doi: 10.1016/j.dmpk.2020.06.008. Epub 2020 Jul 15.
Catalytic interactions of CYP3A4 with large-size ligands have been studied on the Template established in our previous studies using polyaromatic hydrocarbon and steroid ligands (DMPK 34: 113-125 and 351-364 2019 and in press 2020). Typical CYP3A4-substrates including erythromycin, cyclosporin A (ca.1200 Da), ivermectin B1a and taxanes were applied successfully and regioselective metabolisms of these ligands were reconstituted faithfully on Template. These results suggest the applicability of CYP3A4 Template throughout broadened sizes of CYP3A4 ligands. Macrolide antibiotics showed distinct degrees of tight sittings in Width-gauge, a tool for accommodation measure. The observed differences were associated with different inhibitory/inactivation potentials of troleandomycin, erythromycin, clarithromycin and azithromycin, suggesting CYP3A4 Template also as a tool for drug-interaction mechanisms. Slight expansion of Template area was made at near Site of oxidation from simulation results of antitumor agent, rilpivirine, in the present study. Ligand entry from left side of Template is also suggested from macrolide interactions. Broadened applicability of the refined CYP3A4 Template were assured with experiments with various large-size ligands.
CYP3A4 与大尺寸配体的催化相互作用已在我们之前使用多环芳烃和甾体配体（DMPK34：113-125 和 351-364，2019 年和 2020 年即将出版）建立的模板上进行了研究。典型的 CYP3A4 底物包括红霉素、环孢素 A（约 1200 Da）、伊维菌素 B1a 和紫杉烷，这些配体的区域选择性代谢在模板上得到了成功重建。这些结果表明 CYP3A4 模板适用于广泛的 CYP3A4 配体大小。大环内酯类抗生素在宽度计（一种用于容纳度测量的工具）中显示出不同程度的紧密结合。观察到的差异与不同的抑菌/失活潜力有关，包括托罗霉素、红霉素、克拉霉素和阿奇霉素，这表明 CYP3A4 模板也可用作药物相互作用机制的工具。在本研究中，从模拟抗肿瘤药物利匹韦林的结果来看，模板的氧化部位附近的区域略有扩大。从大环内酯类相互作用来看，配体也可以从模板的左侧进入。通过使用各种大尺寸配体进行实验，确保了经过改进的 CYP3A4 模板具有更广泛的适用性。
