College of Pharmaceutical Sciences (Y.W., M.W., H.Q., T.H., J.L., G.H., H.Z.), Institute of Functional Nano and Soft Materials, and Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices (P.P., T.H.), Soochow University, Suzhou, People's Republic of China.
Drug Metab Dispos. 2014 Apr;42(4):782-95. doi: 10.1124/dmd.113.053793. Epub 2014 Jan 29.
Paclitaxel is often used in combination with small molecule kinase inhibitors to enhance antitumor efficacy against various malignancies. Because paclitaxel is metabolized by CYP2C8 and CYP3A4, the possibility of drug-drug interactions mediated by enzyme inhibition may exist between the combining agents. In the present study, a total of 12 kinase inhibitors were evaluated for inhibitory potency in human liver microsomes by monitoring the formation of CYP2C8 and CYP3A4 metabolites simultaneously. For reversible inhibition, nilotinib was found to be the most potent inhibitor against both CYP2C8 and CYP3A4, and the inhibition potency could be explained by strong hydrogen binding based on molecular docking simulations and type II binding based on spectral analysis. Comparison of K(i) values revealed that the CYP2C8 pathway was more sensitive toward some kinase inhibitors (such as axitinib), while the CYP3A4 pathway was preferentially inhibited by others (such as bosutinib). Pathway-dependent inactivation (time-dependent inhibition) was also observed for a number of kinase inhibitors against CYP3A4 but not CYP2C8. Further studies showed that axitinib had a K(I) of 0.93 μM and k(inact) of 0.0137 min(-1), and the observed inactivation toward CYP3A4 was probably due to the formation of reactive intermediate(s). Using a static model, a reasonably accurate prediction of drug-drug interactions was achieved by incorporating parallel pathways and hepatic extraction ratio. The present results suggest that potent and pathway-dependent inhibition of CYP2C8 and/or CYP3A4 pathways by kinase inhibitors may alter the ratio of paclitaxel metabolites in vivo, and that such changes can be clinically relevant as differential metabolism has been linked to paclitaxel-induced neurotoxicity in cancer patients.
紫杉醇常与小分子激酶抑制剂联合使用，以增强对各种恶性肿瘤的抗肿瘤疗效。由于紫杉醇由 CYP2C8 和 CYP3A4 代谢，联合用药之间可能存在由酶抑制介导的药物相互作用的可能性。在本研究中，通过同时监测 CYP2C8 和 CYP3A4 代谢物的形成，评估了总共 12 种激酶抑制剂对人肝微粒体的抑制效力。对于可逆抑制，nilotinib 被发现是对 CYP2C8 和 CYP3A4 最强的抑制剂，并且基于分子对接模拟和光谱分析的 II 型结合，抑制强度可以用强氢键来解释。比较 K(i) 值表明，CYP2C8 途径对一些激酶抑制剂（如 axitinib）更为敏感，而 CYP3A4 途径则对其他抑制剂（如 bosutinib）更为敏感。对 CYP3A4 具有时间依赖性抑制作用（时间依赖性抑制）的激酶抑制剂也有许多，但对 CYP2C8 没有。进一步的研究表明，axitinib 的 K(I) 为 0.93 μM，k(inact)为 0.0137 min(-1)，对 CYP3A4 的观察到的失活可能是由于形成了反应性中间产物。使用静态模型，通过合并平行途径和肝提取率，可以对药物相互作用进行合理准确的预测。这些结果表明，激酶抑制剂对 CYP2C8 和/或 CYP3A4 途径的强和途径依赖性抑制可能会改变体内紫杉醇代谢物的比例，并且这种变化可能具有临床相关性，因为差异代谢与癌症患者紫杉醇引起的神经毒性有关。
