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

CPT: Pharmacometrics and Systems Pharmacology - Tập 8 Số 6 - Trang 396-406 - 2019
Kyoko Nishiyama1, Kota Toshimoto2, Wooin Lee3, Naoki Ishiguro1, Bojan Bister1, Yuichi Sugiyama2
1Pharmacokinetics and Non-Clinical Safety Department, Nippon Boehringer Ingelheim Co., Ltd., Kobe, Hyogo, Japan
2Sugiyama Laboratory, RIKEN Baton Zone Program, RIKEN Cluster for Science, Technology and Innovation Hub, Yokohama, Kanagawa, Japan
3College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea

Tóm tắt

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.

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Tài liệu tham khảo

10.1016/j.ejps.2016.03.020

10.2165/11534750-000000000-00000

10.1007/s10038-006-0087-0

10.2165/00002018-199920040-00006

10.1007/BF00562061

10.1111/j.1365-2125.1981.tb01206.x

10.1007/s00125-013-2991-0

10.1007/s40262-015-0270-6

10.1124/jpet.115.225698

10.1080/00498250701546012

10.1007/s11095-004-1193-3

10.1016/j.bcp.2007.04.010

10.1097/FPC.0b013e32834c0010

10.1097/FPC.0b013e328364a57d

10.1038/clpt.2012.210

10.1111/j.1365-2125.1987.tb03090.x

10.1097/FPC.0b013e328302cd41

10.1007/BF00605632

10.1007/BF00544584

Elsby R., 2017, Mechanistic in vitro studies confirm that inhibition of the renal apical efflux transporter multidrug and toxin extrusion (MATE) 1, and not altered absorption, underlies the increased metformin exposure observed in clinical interactions with cimetidine, trimethoprim or pyrimethamine, Pharmacol. Res. Perspect., 5, 10.1002/prp2.357

10.1124/jpet.111.184986

10.1124/dmd.114.062364

10.1124/jpet.108.146647

10.1002/cpt.391

10.1124/dmd.117.078816

10.1002/jps.20322

10.1124/dmd.115.066647

10.1146/annurev-pharmtox-011112-140309

10.1124/dmd.116.074823

10.1007/978-0-387-72379-2_5

10.1002/bdd.1879

10.2165/00003088-199630050-00003

10.1038/sj.ejcn.1601778

10.1023/A:1023294632129

10.1681/ASN.2006030205

10.1124/mol.109.056242

10.1007/s00228-014-1770-2

10.1113/jphysiol.1949.sp004310

10.1038/clpt.2011.36

10.1111/dom.12577

10.1097/QAI.0000000000000983

10.1111/bcp.12079

10.1007/s40262-014-0161-2

10.1124/jpet.116.236158

10.1111/j.1365-2125.1989.tb05381.x

10.1038/clpt.2013.78

10.2337/diacare.17.10.1100

10.1007/s11095-017-2153-z

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CPT: Pharmacometrics and Systems Pharmacology

Tập 8 Số 6

396-406

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