Department of Drug Metabolism and Pharmacokinetics, Genentech, A Member of the Roche Group, South San Francisco, California, USA.
In Vitro ADMET Laboratories Inc. (IVAL), Columbia, Maryland, USA.
CPT Pharmacometrics Syst Pharmacol. 2018 Apr;7(4):251-258. doi: 10.1002/psp4.12283. Epub 2018 Feb 13.
Plateable human hepatocytes with human plasma were utilized to generate the uptake transporter kinetic data for pravastatin, an organic anion-transporting polypeptide (OATP) transporter substrate. The active hepatic uptake of pravastatin was determined with a J value of 134.4 pmol/min/million cells and K of 76.77 µM in plateable human hepatocytes with human plasma. The physiologically-based pharmacokinetic (PBPK) model with incorporation of these in vitro kinetic data successfully simulated the i.v. pharmacokinetic profile of pravastatin without applying scaling factor (the mean predicted area under the curve (AUC) is within 1.5-fold of the observed). Furthermore, the PBPK model also adequately described the oral plasma concentration-time profiles of pravastatin at different dose levels. The current investigation demonstrates an approach allowing us to build upon the translation of in vitro OATP uptake transporter data to in vivo, with a hope of utilizing the in vitro data for the prospective human pharmacokinetic (PK) prediction.
利用可培养的人源肝细胞和人血浆来生成普伐他汀的摄取转运体动力学数据，普伐他汀是有机阴离子转运多肽（OATP）转运体的底物。在可培养的人源肝细胞和人血浆中，普伐他汀的主动肝摄取的 J 值为 134.4 pmol/min/百万细胞，K 值为 76.77µM。该模型成功模拟了普伐他汀的静脉药代动力学特征，而无需应用比例因子（平均预测 AUC 在观察值的 1.5 倍以内）。此外，该 PBPK 模型还充分描述了普伐他汀在不同剂量水平下的口服血浆浓度-时间曲线。目前的研究表明，我们可以采用一种方法将体外 OATP 摄取转运体数据转化为体内数据，希望能够利用体外数据进行前瞻性的人体药代动力学（PK）预测。
