Association with polymorphic marmoset cytochrome P450 2C19 of in vivo hepatic clearances of chirally separated R-omeprazole and S-warfarin using individual marmoset physiologically based pharmacokinetic models.
Association with polymorphic marmoset cytochrome P450 2C19 of in vivo hepatic clearances of chirally separated R-omeprazole and S-warfarin using individual marmoset physiologically based pharmacokinetic models.
复制标题
使用个体狨猴生理药代动力学模型，与多态狨猴细胞色素 P450 2C19 手性分离的 R-奥美拉唑和 S-华法林体内肝脏清除率相关。
DOI：
10.1080/00498254.2017.1393121
复制
发表时间：
2018
期刊：
影响因子：
1.8
通讯作者：
and Yamazaki H.
中科院分区：
文献类型：
--
作者：
Kusama T;Toda A;Shimizu M;Uehara S;Inoue T;Uno Y;Utoh M;Sasaki E;and Yamazaki H.
1. 最近有报道称，细胞色素P450 2c19和2c9基因型的食虫猴对r -华法林和依非韦伦的模拟清除。为了扩展和验证这一建模过程，使用由肠道、肝脏和中央室组成的个体简化生理药代动力学（PBPK）模型，对单个狨猴口服r / s -奥美拉唑和r / s -华法林的清除率进行了模拟。本研究使用先前报道的血浆微样本手性测定r / s -奥美拉唑的药代动力学。p450 2c19纯合突变体组口服r -奥美拉唑和s -华法林的血药浓度/时间曲线下面积（AUC）显著高于野生型组，s -奥美拉唑和r -华法林的血药浓度/时间曲线下面积（AUC）显著高于野生型组。这些模拟的肝脏内在清除率也与狨猴p450 2c19基因型显著相关。其他参数值，例如吸收率常数或体循环体积，不太可能是决定因素。报告的4-6只狨猴口服r -奥美拉唑和s -华法林后的个体AUC值与虚拟给药后PBPK模型预测的AUC值显著相关。本研究表明，r -奥美拉唑、s -华法林及与P450 2C19多态性相关的相关药物在狨猴个体中的清除率可以通过简化的个体PBPK模型来模拟。
1. Simulated clearances ofR-warfarin and efavirenz were recently reported for individual cynomolgus monkeys genotyped forcytochrome P450 2C19and2C9, respectively. To expand and verify this modeling procedure, simulations ofR/S-omeprazole andR/S-warfarin clearances after oral administrations in individual marmosets were performed using individual simplified physiologically based pharmacokinetic (PBPK) modeling consisting of gut, liver and central compartments.2. Pharmacokinetics ofR/S-omeprazole were chirally determined using the previously reported plasma microsamples in this study. The areas under the plasma concentration/time curves (AUC) ofR-omeprazole andS-warfarin, but notS-omeprazole andR-warfarin, after oral administrations in theP450 2C19homozygous mutant group were significantly higher than those in the wild-type group. These modeled hepatic intrinsic clearances were also significantly associated with the marmosetP450 2C19genotypes. Other parameter values, e.g. absorption rate constants or systemic circulation volumes, were not likely determining factors.3. The reported individual AUC values measured in 4–6 marmosets after oralR-omeprazole andS-warfarin administrations were significantly correlated with the AUC values predicted using the PBPK models after virtual administrations.4. This study indicates that clearances ofR-omeprazole,S-warfarin and related medicines associated with polymorphic P450 2C19 in individual marmosets can be simulated using simplified individual PBPK models.