Mechanism-based inactivation of human cytochrome P450 enzymes and the prediction of drug-drug interactions
Mechanism-based inactivation of human cytochrome P450 enzymes and the prediction of drug-drug interactions
复制标题
DOI：
10.1124/dmd.106.012633
复制
发表时间：
2007-02-01
影响因子：
3.9
通讯作者：
Venkatakrishnan, Karthik
中科院分区：
文献类型：
--
作者：
Obach, R. Scott;Walsky, Robert L.;Venkatakrishnan, Karthik
在合并的人肝微粒体中，使用8种人P450选择性标记物活性，检查了使用体外灭活动力学参数缩放至人细胞色素P450（P450）酶机制灭活剂的体内药物相互作用（DDI）的能力。将这些数据与其他参数（全身C-max、估计的肝脏入口Cmax、未结合分数、根据临床药代动力学数据估计的体内P450酶降解速率常数和被抑制酶清除的受影响药物分数）相结合，以预测药物暴露量的增加，并将预测结果与从科学文献中报告的临床研究中收集的体内DDI进行比较。一般而言，使用未结合的全身Cmax作为体内灭活剂浓度可获得DDI的最准确预测，平均误差倍数为1.64。开发了用于鉴定基于机制的灭活剂的简化体外方法。在不存在和存在NADPH的情况下，在与人肝微粒体预孵育30分钟后，以单一浓度（IC 25）测试潜在灭活剂，然后评估P450标记物活性，很容易鉴别出已知为基于机制的灭活剂的化合物，并代表了一种可用于更大通量的方法。与肝微粒体和NADPH预孵育30 min后IC 50降低的测量结果也可用于鉴定基于机制的灭活剂，并且在此类预孵育后测量的IC 50与完整表征灭活后测量的k（inact）/K-I比值高度相关。总体而言，这些发现支持以下结论：P450体外失活数据在预测可能通过该机制发生的临床DDI方面具有价值。
The ability to use vitro inactivation kinetic parameters in scaling to in vivo drug-drug interactions (DDIs) for mechanism-based inactivators of human cytochrome P450 (P450) enzymes was examined using eight human P450-selective marker activities in pooled human liver microsomes. These data were combined with other parameters (systemic C-max, estimated hepatic inlet Cmax, fraction unbound, in vivo P450 enzyme degradation rate constants estimated from clinical pharmacokinetic data, and fraction of the affected drug cleared by the inhibited enzyme) to predict increases in exposure to drugs, and the predictions were compared with in vivo DDIs gathered from clinical studies reported in the scientific literature. In general, the use of unbound systemic Cmax as the inactivator concentration in vivo yielded the most accurate predictions of DDI with a mean -fold error of 1.64. Abbreviated in vitro approaches to identifying mechanism-based inactivators were developed. Testing potential inactivators at a single concentration (IC25) in a 30-min preincubation with human liver microsomes in the absence and presence of NADPH followed by assessment of P450 marker activities readily identified those compounds known to be mechanism-based inactivators and represents an approach that can be used with greater throughput. Measurement of decreases in IC50 occurring with a 30-min preincubation with liver microsomes and NADPH was also useful in identifying mechanism-based inactivators, and the IC50 measured after such a preincubation was highly correlated with the k(inact)/K-I ratio measured after a full characterization of inactivation. Overall, these findings support the conclusion that P450 in vitro inactivation data are valuable in predicting clinical DDIs that can occur via this mechanism.