Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Simcyp Division, Certara UK Ltd, Sheffield, UK.
CPT Pharmacometrics Syst Pharmacol. 2024 Sep;13(9):1513-1527. doi: 10.1002/psp4.13188. Epub 2024 Jun 19.
OATP1B facilitates the uptake of xenobiotics into hepatocytes and is a prominent target for drug-drug interactions (DDIs). Reduced systemic exposure of OATP1B substrates has been reported following multiple-dose rifampicin; one explanation for this observation is OATP1B induction. Non-uniform hepatic distribution of OATP1B may impact local rifampicin tissue concentrations and rifampicin-mediated protein induction, which may affect the accuracy of transporter- and/or metabolizing enzyme-mediated DDI predictions. We incorporated quantitative zonal OATP1B distribution data from immunofluorescence imaging into a PBPK modeling framework to explore rifampicin interactions with OATP1B and CYP substrates. PBPK models were developed for rifampicin, two OATP1B substrates, pravastatin and repaglinide (also metabolized by CYP2C8/CYP3A4), and the CYP3A probe, midazolam. Simulated hepatic uptake of pravastatin and repaglinide increased from the periportal to the pericentral region (approximately 2.1-fold), consistent with OATP1B distribution data. Simulated rifampicin unbound intracellular concentrations increased in the pericentral region (1.64-fold) compared to simulations with uniformly distributed OATP1B. The absolute average fold error of the rifampicin PBPK model for predicting substrate maximal concentration (C) and area under the plasma concentration-time curve (AUC) ratios was 1.41 and 1.54, respectively (nine studies). In conclusion, hepatic OATP1B distribution has a considerable impact on simulated zonal substrate uptake clearance values and simulated intracellular perpetrator concentrations, which regulate transporter and metabolic DDIs. Additionally, accounting for rifampicin-mediated OATP1B induction in parallel with inhibition improved model predictions. This study provides novel insight into the effect of hepatic OATP1B distribution on site-specific DDI predictions and the impact of accounting for zonal transporter distributions within PBPK models.
OATP1B 有助于外源性物质进入肝细胞，是药物-药物相互作用（DDI）的主要靶点。利福平多次给药后，OATP1B 底物的全身暴露减少；这种观察结果的一种解释是 OATP1B 诱导。OATP1B 的非均匀肝分布可能会影响局部利福平组织浓度和利福平介导的蛋白诱导，这可能会影响转运体和/或代谢酶介导的 DDI 预测的准确性。我们将来自免疫荧光成像的定量区域 OATP1B 分布数据纳入 PBPK 建模框架，以探讨利福平与 OATP1B 和 CYP 底物的相互作用。为利福平、两种 OATP1B 底物普伐他汀和瑞格列奈（也被 CYP2C8/CYP3A4 代谢）以及 CYP3A 探针咪达唑仑开发了 PBPK 模型。普伐他汀和瑞格列奈的模拟肝摄取从门周区向中央区增加（约 2.1 倍），与 OATP1B 分布数据一致。与均匀分布的 OATP1B 相比，模拟利福平未结合细胞内浓度在中央区增加（1.64 倍）。预测底物最大浓度（C）和血浆浓度-时间曲线下面积（AUC）比值的利福平 PBPK 模型的绝对平均折叠误差分别为 1.41 和 1.54（九项研究）。总之，肝 OATP1B 分布对模拟区域底物摄取清除值和调节转运体和代谢 DDI 的模拟细胞内致剂浓度有很大影响。此外，平行考虑利福平介导的 OATP1B 诱导和抑制作用可改善模型预测。这项研究为肝 OATP1B 分布对特定部位 DDI 预测的影响以及在 PBPK 模型中考虑区域转运体分布的影响提供了新的见解。
