Primary human hepatocytes as a tool for the evaluation of structure-activity relationship in cytochrome P450 induction potential of xenobiotics: evaluation of rifampin, rifapentine and rifabutin
Primary human hepatocytes as a tool for the evaluation of structure-activity relationship in cytochrome P450 induction potential of xenobiotics: evaluation of rifampin, rifapentine and rifabutin
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DOI：
10.1016/s0009-2797(97)00071-9
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发表时间：
1997-11-06
影响因子：
5.1
通讯作者：
Cheng, LK
中科院分区：
文献类型：
--
作者：
Li, AP;Reith, MK;Cheng, LK
在我们的实验室中，原代人肝细胞正在作为体外实验系统进行研究，用于评价药代动力学药物-药物相互作用。我们的研究首次报道了直接比较利福霉素B衍生的三种抗菌药物（即利福平、利福喷丁和利福贝汀）的细胞色素P450同工酶3A（CYP 3A）诱导潜力的研究。使用了CYP 3A活性的两个终点，睾酮6 β-羟基化和咪达唑仑1-羟基化。从四个不同的人供体肝细胞获得的结果一致表明，利福平和利福喷丁是CYP 3A的强效诱导剂，而观察到利福布雷定的诱导潜力显著较低。三种抗微生物剂的相对诱导效力（利福平>利福喷丁，远大于利福贝汀）与可用的人体体内数据一致。对于CYP 1A（以乙氧基试卤灵O-脱乙基酶活性测量）、CYP 2C 8/9（以甲苯磺丁脲4-羟基化活性测量）、CYP 2D 6（以美沙芬O-脱甲基化测量）和AZT葡萄糖醛酸化，无影响或！当发现诱导在这些其他终点中具有统计学显著性时，最大诱导值始终<对照的100%。我们的结果表明，CYP 3A是这些利福霉素B衍生物诱导的主要酶。这些研究说明了人肝细胞在评价这类化学品的抗肿瘤诱导的构效关系中的应用，以及作为通过CTP诱导的药物-药物相互作用潜力的体外筛选。(C)1997 Elsevier Science爱尔兰有限公司
In our laboratory, primary human hepatocytes are being investigated as an in vitro experimental system for the evaluation of pharmacokinetic drug-drug interactions. Our study here represents the first reported study that directly compares the cytochrome P450 isozyme 3A (CYP3A) induction potential of three antimicrobials derived from rifamycin B, namely, rifampin, rifapentine and rifabutin. Two endpoints of CYP3A activity, testosterone 6 beta-hydroxylation and midazolam 1-hydroxylation have been used. Results obtained with hepatocytes from four different human donors show consistently that rifampin and rifapentine are potent inducers of CYP3A, while a significantly lower induction potential is observed for rifabutin. The relative induction potency of the three antimicrobials (rifampin > rifapentine much greater than rifabutin) is consistent with the available human in vivo data. For CYP1A measured as ethoxyresorufin O-deethylase activity, CYP2C8/9 measured as tolbutamide 4-hydroxylation activity, CYP2D6 measured as dextromethorphan O-demethylation, and AZT glucuronidation, there is either no effect or! where induction is found to be statistically significant in these other endpoints, the maximum induction values are consistently < 100% of the control. Our results suggest that CYP3A is the major CYP induced by these rifamycin B derivatives. These studies illustrate the application of human hepatocytes in the evaluation of the structure-activity relationships in CYP induction for this class of chemicals and as an in vitro screen for drug-drug interaction potential via CTP induction. (C) 1997 Elsevier Science Ireland Ltd.