The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
Department of Pharmacology, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China.
Basic Clin Pharmacol Toxicol. 2018 Apr;122(4):383-387. doi: 10.1111/bcpt.12934. Epub 2017 Nov 30.
Cytochrome P450 3A4 (CYP3A4) is quantitatively the most important P450 enzyme in adults. It is suggested that CYP3A4 genetic polymorphisms may influence the rate of the metabolism and elimination of CYP3A4 substrates in human beings. Ibrutinib is an anticancer drug and primarily metabolized by CYP3A4. The aim of this study was to systematically investigate the effects of 22 CYP3A4 protein variants on the metabolism of ibrutinib in vitro. When compared with wild-type CYP3A4.1, two variants (CYP3A4.17 and CYP3A4.24) had no detectable enzyme activity; five variants (CYP3A4.10, .11, .18, .23 and .33) exhibited no significant differences; another five variants (CYP3A4.3, .4, .9, .19 and .34) showed increased intrinsic clearance values, while the remaining nine variants (CYP3A4.2, .5, .14, .15, .16, .28, .29, .31 and .32) displayed decreased enzymatic activities in different degrees. As the first study of 22 CYP3A4 protein variants in ibrutinib metabolism, these comprehensive data may help in the clinical assessment of the metabolism and elimination of ibrutinib and also offer a reference to the personalized treatment of ibrutinib in clinic.
细胞色素 P450 3A4（CYP3A4）在成人中是数量最多的最重要的 P450 酶。据推测，CYP3A4 遗传多态性可能影响 CYP3A4 底物在人体内的代谢和消除速度。依鲁替尼是一种抗癌药物，主要由 CYP3A4 代谢。本研究旨在系统研究 22 种 CYP3A4 蛋白变体对依鲁替尼体外代谢的影响。与野生型 CYP3A4.1 相比，两种变体（CYP3A4.17 和 CYP3A4.24）没有检测到酶活性；五种变体（CYP3A4.10、.11、.18、.23 和.33）没有显著差异；另外五种变体（CYP3A4.3、.4、.9、.19 和.34）显示出增加的内在清除率值，而其余九个变体（CYP3A4.2、.5、.14、.15、.16、.28、.29、.31 和.32）则显示出不同程度的酶活性降低。作为依鲁替尼代谢中 22 种 CYP3A4 蛋白变体的第一项研究，这些综合数据可能有助于对依鲁替尼的代谢和消除进行临床评估，并为依鲁替尼的临床个体化治疗提供参考。
