Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
J Pharmacokinet Pharmacodyn. 2010 Dec;37(6):575-90. doi: 10.1007/s10928-010-9176-y. Epub 2010 Nov 10.
This review illustrates the concept of a rate-determining process in the overall hepatic elimination of anionic drugs that involves transporters in the uptake process. A kinetic study in rats has demonstrated that uptake is the rate-determining process for most anionic drugs, and this is likely to hold true for the hepatic elimination of statins in humans. To simulate the effects of variations in the transporter activities on systemic and liver exposure, a physiologically based pharmacokinetic model was constructed for pravastatin, the overall elimination of which involves OATP1B1 and MRP2 in the hepatic uptake and canalicular efflux, respectively. The plasma concentrations of pravastatin in humans were successfully reproduced using the kinetic parameters extrapolated from in vitro data obtained using human hepatocytes and canalicular membrane vesicles and the scaling factors determined in rats. Sensitivity analyses showed that a variation in hepatic uptake altered the plasma concentration of pravastatin markedly, but had a small effect on the liver concentration, and vice versa for the canalicular efflux. Therefore, variation in the OATP1B1 activities will have small and large impacts on the therapeutic efficacy and adverse effect (myopathy) of pravastatin, respectively, whereas that affecting the MRP2 activities may have an opposite effect (i.e., large and small impacts on the therapeutic efficacy and side effect). This pharmacokinetic characteristics likely hold true for other anionic statins, i.e., variation of OATP1B1 is associated with the risk of adverse reactions, whereas that of sequestration mechanisms causes the variation of their pharmacological effect.
本文综述了阴离子药物在肝脏整体消除过程中涉及摄取过程中转运体的限速步骤概念。一项在大鼠中的动力学研究表明，摄取是大多数阴离子药物的限速步骤，这对于人类他汀类药物的肝脏消除也可能是正确的。为了模拟转运体活性变化对全身和肝脏暴露的影响，构建了普伐他汀的基于生理学的药代动力学模型，其整体消除分别涉及肝脏摄取中的 OATP1B1 和 MRP2 以及胆汁排泄。使用从人肝细胞和胆管膜囊泡获得的体外数据外推的动力学参数以及在大鼠中确定的标化因子，成功地再现了普伐他汀在人体内的血浆浓度。敏感性分析表明，肝脏摄取的变化显著改变了普伐他汀的血浆浓度，但对肝脏浓度的影响较小，而胆汁排泄则相反。因此，OATP1B1 活性的变化将分别对普伐他汀的治疗效果和不良反应（肌病）产生小的和大的影响，而影响 MRP2 活性的变化可能产生相反的影响（即，治疗效果和副作用的大的和小的影响）。这种药代动力学特征可能适用于其他阴离子他汀类药物，即 OATP1B1 的变化与不良反应的风险相关，而摄取机制的变化导致其药理作用的变化。
