The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China; Institute of Molecular Toxicology and Pharmacology, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
Biomed Pharmacother. 2023 Dec;168:115833. doi: 10.1016/j.biopha.2023.115833. Epub 2023 Nov 6.
The aim of this study was to investigate the impacts of 24 variants of recombinant human CYP3A4 and drug interactions on the metabolism of lurasidone. In vitro, enzymatic reaction incubation system of CYP3A4 was established to determine the kinetic parameters of lurasidone catalyzed by 24 CYP3A4 variants. Then, we constructed rat liver microsomes (RLM) and human liver microsomes (HLM) incubation system to screen potential anti-tumor drugs that could interact with lurasidone and studied its inhibitory mechanism. In vivo, Sprague-Dawley (SD) rats were applied to study the interaction between lurasidone and olmutinib. The concentrations of the analytes were detected by ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). As the results, we found that compared with the wild-type CYP3A4, the relative intrinsic clearances vary from 355.77 % in CYP3A4.15 to 14.11 % in CYP3A4.12. A series of drugs were screened based on the incubation system, and compared to without olmutinib, the amount of ID-14283 (the metabolite of lurasidone) in RLM and HLM were reduced to 7.22 % and 7.59 %, and its IC were 18.83 ± 1.06 μM and 16.15 ± 0.81 μM, respectively. At the same time, it exerted inhibitory effects both through a mixed mechanism. When co-administration of lurasidone with olmutinib in rats, the AUC and AUC of lurasidone were significantly increased by 73.52 % and 69.68 %, respectively, while CL was observably decreased by 43.83 %. In conclusion, CYP3A4 genetic polymorphism and olmutinib can remarkably affect the metabolism of lurasidone.
本研究旨在探讨 24 种重组人 CYP3A4 变体和药物相互作用对鲁拉西酮代谢的影响。在体外，建立了 CYP3A4 的酶反应孵育系统，以确定 24 种 CYP3A4 变体催化鲁拉西酮的动力学参数。然后，我们构建了大鼠肝微粒体（RLM）和人肝微粒体（HLM）孵育系统，以筛选可能与鲁拉西酮相互作用的潜在抗肿瘤药物，并研究其抑制机制。在体内，应用 Sprague-Dawley（SD）大鼠研究鲁拉西酮与奥希替尼的相互作用。通过超高效液相色谱串联质谱（UPLC-MS/MS）检测分析物的浓度。结果发现，与野生型 CYP3A4 相比，相对内在清除率在 CYP3A4.15 中高达 355.77%，在 CYP3A4.12 中低至 14.11%。基于孵育系统筛选了一系列药物，与无奥希替尼相比，RLM 和 HLM 中 ID-14283（鲁拉西酮的代谢物）的量减少到 7.22%和 7.59%，其 IC50 分别为 18.83±1.06μM 和 16.15±0.81μM。同时，它通过混合机制发挥抑制作用。当鲁拉西酮与奥希替尼在大鼠体内同时给药时，鲁拉西酮的 AUC 和 AUC 分别显著增加 73.52%和 69.68%，而 CL 则明显降低 43.83%。总之，CYP3A4 遗传多态性和奥希替尼可显著影响鲁拉西酮的代谢。
