Physiologically-Based Pharmacokinetic Modeling Analysis for Quantitative Prediction of Renal Transporter-Mediated Interactions Between Metformin and Cimetidine
Physiologically-Based Pharmacokinetic Modeling Analysis for Quantitative Prediction of Renal Transporter-Mediated Interactions Between Metformin and Cimetidine
复制标题
DOI：
10.1002/psp4.12398
复制
发表时间：
2019-06-01
影响因子：
3.5
通讯作者：
Sugiyama, Yuichi
中科院分区：
文献类型：
--
作者：
Nishiyama, Kotaro;Toshimoto, Kota;Sugiyama, Yuichi
二甲双胍是一种重要的抗糖尿病药物，常用作肾转运蛋白介导的药物相互作用（DDI）的探针。尽管有证据支持多药和毒素外排蛋白的抑制是可能的DDI机制，但先前报告的基于生理学的药代动力学（PBPK）模型需要从体外获得的抑制常数中大幅降低西咪替丁对多药和毒素外排蛋白的抑制常数，以获取二甲双胍和西咪替丁之间的临床DDI数据。(1)我们构建了新的PBPK模型，其中转运蛋白介导的二甲双胍摄取由恒定的膜电位驱动。我们的模型成功地捕获了临床DDI数据，在体外抑制恒定值，并支持通过西咪替丁作为DDI机制的敏感性分析和数据拟合的多药和毒素挤出蛋白的抑制。我们改进的PBPK模型可能有助于使用体外抑制常数值预测涉及二甲双胍的DDI。
Metformin is an important antidiabetic drug and often used as a probe for drug-drug interactions (DDIs) mediated by renal transporters. Despite evidence supporting the inhibition of multidrug and toxin extrusion proteins as the likely DDI mechanism, the previously reported physiologically-based pharmacokinetic (PBPK) model required the substantial lowering of the inhibition constant values of cimetidine for multidrug and toxin extrusion proteins from those obtained in vitro to capture the clinical DDI data between metformin and cimetidine.(1) We constructed new PBPK models in which the transporter-mediated uptake of metformin is driven by a constant membrane potential. Our models successfully captured the clinical DDI data using in vitro inhibition constant values and supported the inhibition of multidrug and toxin extrusion proteins by cimetidine as the DDI mechanism upon sensitivity analysis and data fitting. Our refined PBPK models may facilitate prediction approaches for DDI involving metformin using in vitro inhibition constant values.