Gao Nanyong, Zhang Xiaodan, Hu Xiaoqin, Kong Qihui, Cai Jianping, Hu Guoxin, Qian Jianchang
Institute of Molecular Toxicology and Pharmacology, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China.
The Seventh People's Hospital of Wenzhou, Wenzhou, China.
Front Pharmacol. 2022 Mar 10;13:794931. doi: 10.3389/fphar.2022.794931. eCollection 2022.
The aim of this study was to 1) investigate the effects of 27 CYP3A4 variants on the metabolism of osimertinib and 2) study the interactions between osimertinib and others as well as the underlying mechanism. A recombinant human CYP3A4 enzymatic incubation system was developed and employed to determine the kinetic profile of CYP3A4 variants. Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was applied to detect the concentration of the main metabolite, AZ5104. The results demonstrated that the relative clearance rates of CYP3A4.19, 10, 18, 5, 16, 14, 11, 2, 13, 12, 7, 8, and 17 in catalyzing osimertinib were significantly reduced to a minimum of 25.68% compared to CYP3A4.1, while those of CYP3A4.29, 32, 33, 28, 15, 34, and 3 were obviously enhanced, ranging from 114.14% to 284.52%. The activities of the remaining variants were almost equal to those of CYP3A4.1. In addition, 114 drugs were screened to determine the potential interaction with osimertinib based on the rat liver microsome (RLM) reaction system. Sixteen of them inhibited the production of AZ5104 to 20% or less, especially proton pump inhibitors, among which the IC of rabeprazole was 6.49 ± 1.17 μM in RLM and 20.39 ± 2.32 μM in human liver microsome (HLM), with both following competitive and non-competitive mixed mechanism. In an study, Sprague-Dawley (SD) rats were randomly divided into groups, with six animals per group, receiving osimertinib with or without rabeprazole, omeprazole, and lansoprazole. We found that the AUC, AUC, and C of osimertinib decreased significantly after co-administration with rabeprazole orally, but they increased remarkably when osimertinib was administered through intraperitoneal injection. Taken together, our data demonstrate that the genetic polymorphism and proton pump inhibitors remarkably influence the disposition of osimertinib, thereby providing basic data for the precise application of osimertinib.
1）研究27种CYP3A4变体对奥希替尼代谢的影响；2）研究奥希替尼与其他药物之间的相互作用及其潜在机制。建立了重组人CYP3A4酶孵育系统并用于测定CYP3A4变体的动力学特征。采用超高效液相色谱-串联质谱法（UPLC-MS/MS）检测主要代谢产物AZ5104的浓度。结果表明，与CYP3A4.1相比，CYP3A4.19、10、18、5、16、14、11、2、13、12、7、8和17催化奥希替尼的相对清除率显著降低，最低降至25.68%，而CYP3A4.29、32、33、28、15、34和3的相对清除率明显提高，范围为114.14%至284.52%。其余变体的活性几乎与CYP3A4.1相等。此外，基于大鼠肝微粒体（RLM）反应系统筛选了114种药物，以确定其与奥希替尼的潜在相互作用。其中16种药物将AZ5104的生成抑制至20%或更低，尤其是质子泵抑制剂，其中雷贝拉唑在RLM中的IC为6.49±1.17 μM，在人肝微粒体（HLM）中的IC为20.39±2.32 μM，两者均遵循竞争性和非竞争性混合机制。在一项研究中，将Sprague-Dawley（SD）大鼠随机分为几组，每组6只动物，分别接受奥希替尼加或不加雷贝拉唑、奥美拉唑和兰索拉唑。我们发现，口服雷贝拉唑后，奥希替尼的AUC、AUC和C显著降低，但腹腔注射奥希替尼时，它们显著升高。综上所述，我们的数据表明，基因多态性和质子泵抑制剂显著影响奥希替尼的处置，从而为奥希替尼的精准应用提供基础数据。
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