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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.

cpt: pharmacometrics and systems pharmacology

Physiologically‐Based Pharmacokinetic Modeling Analysis for Quantitative Prediction of Renal Transporter–Mediated Interactions Between Metformin and Cimetidine