Department of Pharmaceutics, School of Pharmacy, University of Washington, University of Washington, Seattle, WA, USA.
Drug Metab Dispos. 2013 Jul;41(7):1414-24. doi: 10.1124/dmd.113.051722. Epub 2013 Apr 25.
The aim of this study was to evaluate the contribution of metabolites to drug-drug interactions (DDI) using the inhibition of CYP2C19 and CYP3A4 by omeprazole and its metabolites as a model. Of the metabolites identified in vivo, 5-hydroxyomeprazole, 5'-O-desmethylomeprazole, omeprazole sulfone, and carboxyomeprazole had a metabolite to parent area under the plasma concentration-time curve (AUC(m)/AUC(p)) ratio ≥ 0.25 when either total or unbound concentrations were measured after a single 20-mg dose of omeprazole in a cocktail. All of the metabolites inhibited CYP2C19 and CYP3A4 reversibly. In addition omeprazole, omeprazole sulfone, and 5'-O-desmethylomeprazole were time dependent inhibitors (TDI) of CYP2C19, whereas omeprazole and 5'-O-desmethylomeprazole were found to be TDIs of CYP3A4. The in vitro inhibition constants and in vivo plasma concentrations were used to evaluate whether characterization of the metabolites affected DDI risk assessment. Identifying omeprazole as a TDI of both CYP2C19 and CYP3A4 was the most important factor in DDI risk assessment. Consideration of reversible inhibition by omeprazole and its metabolites would not identify DDI risk with CYP3A4, and with CYP2C19, reversible inhibition values would only identify DDI risk if the metabolites were included in the assessment. On the basis of inactivation data, CYP2C19 and CYP3A4 inhibition by omeprazole would be sufficient to identify risk, but metabolites were predicted to contribute 30-63% to the in vivo hepatic interactions. Therefore, consideration of metabolites may be important in quantitative predictions of in vivo DDIs. The results of this study show that, although metabolites contribute to in vivo DDIs, their relative abundance in circulation or logP values do not predict their contribution to in vivo DDI risk.
本研究旨在评估代谢物对药物相互作用（DDI）的贡献，采用奥美拉唑及其代谢物抑制 CYP2C19 和 CYP3A4 作为模型。在体内鉴定的代谢物中，当奥美拉唑单剂量 20mg 后测量总浓度或游离浓度时，5-羟奥美拉唑、5'-O-去甲奥美拉唑、奥美拉唑砜和羧酸奥美拉唑的代谢物与母体的血药浓度-时间曲线下面积比值（AUC(m)/AUC(p)）≥0.25。所有代谢物均可逆抑制 CYP2C19 和 CYP3A4。此外，奥美拉唑、奥美拉唑砜和 5'-O-去甲奥美拉唑是 CYP2C19 的时间依赖性抑制剂（TDI），而奥美拉唑和 5'-O-去甲奥美拉唑被发现是 CYP3A4 的 TDI。体外抑制常数和体内血浆浓度用于评估代谢物的特征是否影响 DDI 风险评估。将奥美拉唑鉴定为 CYP2C19 和 CYP3A4 的 TDI 是 DDI 风险评估中最重要的因素。考虑奥美拉唑及其代谢物的可逆抑制作用不会识别 CYP3A4 的 DDI 风险，而对于 CYP2C19，只有在评估中包含代谢物时，可逆抑制值才会识别 DDI 风险。基于失活数据，奥美拉唑对 CYP2C19 和 CYP3A4 的抑制作用足以识别风险，但代谢物预计将对体内肝相互作用贡献 30-63%。因此，考虑代谢物可能对体内 DDI 的定量预测很重要。本研究结果表明，尽管代谢物会导致体内 DDI，但它们在循环中的相对丰度或 logP 值并不能预测其对体内 DDI 风险的贡献。
