A Semi-Mechanistic Metabolism Model of CYP3A Substrates in Pregnancy: Predicting Changes in Midazolam and Nifedipine Pharmacokinetics.
A Semi-Mechanistic Metabolism Model of CYP3A Substrates in Pregnancy: Predicting Changes in Midazolam and Nifedipine Pharmacokinetics.
复制标题
妊娠中CYP3A底物的半机械代谢模型：预测咪达唑仑和硝苯地平药代动力学的变化。
DOI：
10.1038/psp.2012.5
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发表时间：
2012-09-26
影响因子：
3.5
通讯作者：
Li, L
中科院分区：
文献类型：
--
作者：
Quinney, S K;Mohamed, A N;Hebert, M F;Haas, D M;Clark, S;Umans, J G;Caritis, S N;Li, L
怀孕期间的生理变化，包括身体组成和代谢酶活性的变化，可以改变药物的药代动力学。建立半机制代谢模型，描述两种细胞色素P450 3A （CYP3A）底物咪达唑仑和硝苯地平在产科患者中的药代动力学。优化模型参数，拟合孕妇口服咪达唑仑药代动力学数据，在不改变肠壁代谢的情况下，将cyp3a诱导的肝脏代谢增加1.6倍。胎儿代谢对母体血浆药物浓度的影响可以忽略不计。通过将体积分布和代谢的变化与咪达唑仑观察到的一致应用于健康志愿者体内速释硝苯地平的药代动力学参数来验证该模型。硝苯地平在浓度-时间曲线（auc）下的预测稳态区域与接受早产治疗的孕妇观察到的数据在15%以内。该模型预测了两种CYP3A底物在妊娠期的药代动力学，也可能适用于其他CYP3A底物。
Physiological changes in pregnancy, including changes in body composition and metabolic enzyme activity, can alter drug pharmacokinetics. A semi-mechanistic metabolism model was developed to describe the pharmacokinetics of two cytochrome P450 3A (CYP3A) substrates, midazolam and nifedipine, in obstetrics patients. The model parameters were optimized to fit the data of oral midazolam pharmacokinetics in pregnant women, by increasing CYP3A-induced hepatic metabolism 1.6-fold in the model with no change in gut wall metabolism. Fetal metabolism had a negligible effect on maternal plasma drug concentrations. Validation of the model was performed by applying changes in volume of distribution and metabolism, consistent with those observed for midazolam, to the pharmacokinetics parameters of immediate-release nifedipine in healthy volunteers. The predicted steady-state areas under the concentration–time curve (AUCs) for nifedipine were within 15% of the data observed in pregnant women undergoing treatment for preterm labor. This model predicts the pharmacokinetics of two CYP3A substrates in pregnancy, and may be applicable to other CYP3A substrates as well.