Physiologically Based Pharmacokinetic Modeling to Predict Transporter-Mediated Clearance and Distribution of Pravastatin in Humans
Physiologically Based Pharmacokinetic Modeling to Predict Transporter-Mediated Clearance and Distribution of Pravastatin in Humans
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DOI：
10.1124/jpet.108.146647
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发表时间：
2009-02-01
影响因子：
3.5
通讯作者：
Sugiyama, Yuichi
中科院分区：
文献类型：
--
作者：
Watanabe, Takao;Kusuhara, Hiroyuki;Sugiyama, Yuichi
由转运蛋白、有机阴离子转运多肽 (OATP) 1B1 和多药耐药相关蛋白 (MRP) 2 介导的肝胆排泄是 HMG-CoA 还原酶抑制剂普伐他汀的主要消除途径。本研究使用基于生理学的药代动力学模型检查了转运蛋白活性的变化对普伐他汀全身和肝脏暴露的影响。通过比较大鼠体内和体外普伐他汀的肝摄取和小管流出参数来确定缩放因子。模拟的血浆和肝脏浓度以及胆汁排泄曲线非常接近线性和非线性条件下大鼠的观察数据。使用在大鼠中获得的缩放因子，将在人冷冻保存的肝细胞和小管膜囊泡中测定的体外参数外推到体内参数。普伐他汀的模拟血浆浓度接近人类报告的值。敏感性分析显示，肝脏摄取能力的变化显着改变了普伐他汀的血浆浓度，但对肝脏浓度的影响很小，而小管流出能力的变化显着改变了普伐他汀的肝脏浓度，但对血浆浓度的影响较小。总之，该模型可以预测普伐他汀在人体中的分布。本研究表明，OATP1B1活性的变化可能分别对普伐他汀的治疗效果和副作用（肌病）产生小和大的影响，而MRP2活性的变化可能产生相反的影响（即对治疗效果和副作用影响大和小）。
Hepatobiliary excretion mediated by transporters, organic anion-transporting polypeptide (OATP) 1B1 and multidrug resistance-associated protein (MRP) 2, is the major elimination pathway of an HMG-CoA reductase inhibitor, pravastatin. The present study examined the effects of changes in the transporter activities on the systemic and liver exposure of pravastatin using a physiologically based pharmacokinetic model. Scaling factors, determined by comparing in vivo and in vitro parameters of pravastatin in rats for the hepatic uptake and canalicular efflux, were obtained. The simulated plasma and liver concentrations and biliary excretion profiles were very close to the observed data in rats under linear and nonlinear conditions. In vitro parameters, determined in human cryopreserved hepatocytes and canalicular membrane vesicles, were extrapolated to in vivo parameters using the scaling factors obtained in rats. The simulated plasma concentrations of pravastatin were close to the reported values in humans. Sensitivity analyses showed that changes in the hepatic uptake ability altered the plasma concentration of pravastatin markedly but had a minimal effect on the liver concentration, whereas changes in the ability of canalicular efflux altered the liver concentration of pravastatin markedly but had a small effect on the plasma concentration. In conclusion, the model allows the prediction of the disposition of pravastatin in humans. The present study suggests that changes in the OATP1B1 activities may have a small and a large impact on the therapeutic efficacy and side effect ( myopathy) of pravastatin, respectively, whereas those in the MRP2 activities may have opposite impacts (i.e., large and small impacts on the therapeutic efficacy and side effect).