Sugiyama Laboratory, RIKEN Innovation Center, RIKEN, Yokohama, Kanagawa, Japan.
Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan.
Clin Pharmacol Ther. 2016 Nov;100(5):513-523. doi: 10.1002/cpt.391. Epub 2016 Jul 28.
This study aimed to construct a widely applicable method for quantitative analyses of drug-drug interactions (DDIs) caused by the inhibition of hepatic organic anion transporting polypeptides (OATPs) using physiologically based pharmacokinetic (PBPK) modeling. Models were constructed for pitavastatin, fluvastatin, and pravastatin as substrates and cyclosporin A (CsA) and rifampicin (RIF) as inhibitors, where enterohepatic circulations (EHC) of statins were incorporated. By fitting to clinical data, parameters that described absorption, hepatic elimination, and EHC processes were optimized, and the extent of these DDIs was explained satisfactorily. Similar in vivo inhibition constant (K ) values of each inhibitor against OATPs were obtained, regardless of the substrates. Estimated K values of CsA were comparable to reported in vitro values with the preincubation of CsA, while those of RIF were smaller than reported in vitro values (coincubation). In conclusion, this study proposes a method to optimize in vivo PBPK parameters in hepatic uptake transporter-mediated DDIs.
本研究旨在构建一种广泛适用于定量分析药物-药物相互作用（DDI）的方法，该方法基于药代动力学（PBPK）模型，用于抑制肝有机阴离子转运多肽（OATPs）。本研究构建了作为底物的匹伐他汀、氟伐他汀和普伐他汀，以及作为抑制剂的环孢素 A（CsA）和利福平（RIF）的模型，其中纳入了他汀类药物的肠肝循环（EHC）。通过拟合临床数据，对描述吸收、肝消除和 EHC 过程的参数进行了优化，并对这些 DDI 的程度进行了满意的解释。无论底物如何，每个抑制剂对 OATPs 的体内抑制常数（K ）值均相似。与 CsA 的预孵育相比，估算的 CsA 的 K 值与报道的体外值相当，而 RIF 的 K 值则小于报道的体外值（共孵育）。总之，本研究提出了一种优化肝摄取转运体介导的 DDI 中体内 PBPK 参数的方法。
