Improved Predictions of Drug-Drug Interactions Mediated by Time-Dependent Inhibition of CYP3A.
Improved Predictions of Drug-Drug Interactions Mediated by Time-Dependent Inhibition of CYP3A.
复制标题
DOI：
10.1021/acs.molpharmaceut.8b00129
复制
发表时间：
2018-05-07
影响因子：
4.9
通讯作者：
Nagar S
中科院分区：
文献类型：
--
作者：
Yadav J;Korzekwa K;Nagar S
细胞色素P450（CYP）的时间依赖性失活（TDI）是临床药物相互作用（DDI）的主要原因。目前的方法倾向于过度预测DDI。在这项研究中，使用数值方法来模拟复杂的CYP 3A TDI在人肝微粒体。评价的抑制剂包括醋竹桃霉素（TAO）、红霉素（ERY）、维拉帕米（VER）和地尔硫卓（DTZ）沿着主要代谢物N-去甲基红霉素（NDE）、去甲维拉帕米（NV）和N-去甲基地尔硫卓（NDD）。模型中纳入的复杂性包括多重结合动力学、准不可逆失活、顺序代谢、抑制剂耗尽和膜分配。将所得灭活参数纳入静态体外-体内相关性（IVIVC）模型中，以预测临床DDI。对于77个临床观察到的DDI，肝脏CYP 3A合成速率常数为0.000 146 min−1，标准重绘法观察到的DDI与预测DDI之间的平均倍数差为3.17，数值法为1.45。使用0.000 32 min−1的合成速率常数获得了类似的结果。这些结果表明，数值方法可以成功地模拟复杂的体外TDI动力学，并得到的DDI预测是更准确的比那些获得的标准重绘图方法。
Time-dependent inactivation (TDI) of cytochrome P450s (CYPs) is a leading cause of clinical drug–drug interactions (DDIs). Current methods tend to overpredict DDIs. In this study, a numerical approach was used to model complex CYP3A TDI in human-liver microsomes. The inhibitors evaluated included troleandomycin (TAO), erythromycin (ERY), verapamil (VER), and diltiazem (DTZ) along with the primary metabolites N-demethyl erythromycin (NDE), norverapamil (NV), and N-desmethyl diltiazem (NDD). The complexities incorporated into the models included multiple-binding kinetics, quasi-irreversible inactivation, sequential metabolism, inhibitor depletion, and membrane partitioning. The resulting inactivation parameters were incorporated into static in vitro–in vivo correlation (IVIVC) models to predict clinical DDIs. For 77 clinically observed DDIs, with a hepatic-CYP3A-synthesis-rate constant of 0.000 146 min−1, the average fold difference between the observed and predicted DDIs was 3.17 for the standard replot method and 1.45 for the numerical method. Similar results were obtained using a synthesis-rate constant of 0.000 32 min−1. These results suggest that numerical methods can successfully model complex in vitro TDI kinetics and that the resulting DDI predictions are more accurate than those obtained with the standard replot approach.
登录
查看更多内容
影响因子：
3.9
作者：
Fahmi, Odette A.;Hurst, Susan;Obach, R. Scott
通讯作者：
Obach, R. Scott
影响因子：
6.7
作者：
Cheng, CL;Smith, DE;Stetson, PL
通讯作者：
Stetson, PL
影响因子：
2.9
作者：
CUSACK, B;OMALLEY, K;KELLY, JG
通讯作者：
KELLY, JG
影响因子：
2.9
作者：
DANHOF, M;VANZUILEN, A;BREIMER, DD
通讯作者：
BREIMER, DD
影响因子：
6.7
作者：
BARGETZI, MJ;AOYAMA, T;MEYER, UA
通讯作者：
MEYER, UA