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

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 phar...

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Bibliographic Details
Published in:CPT: pharmacometrics and systems pharmacology 2019-06, Vol.8 (6), p.396-406
Main Authors: Nishiyama, Kotaro, Toshimoto, Kota, Lee, Wooin, Ishiguro, Naoki, Bister, Bojan, Sugiyama, Yuichi
Format: Article
Language:English
Subjects:
Antidiabetics
Blood
Drug dosages
Liver
Pharmacokinetics
Physiology
Proteins
Urine
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Summary: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.
ISSN:2163-8306
2163-8306
DOI:10.1002/psp4.12398