Proton Pump Inhibitors Inhibit Metformin Uptake by Organic Cation Transporters (OCTs)

Metformin, an oral insulin-sensitizing drug, is actively transported into cells by organic cation transporters (OCT) 1, 2, and 3 (encoded by SLC22A1, SLC22A2, or SLC22A3), which are tissue specifically expressed at significant levels in various organs such as liver, muscle, and kidney. Because metfo...

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Main Authors:	Nies, Anne T., Hofmann, Ute, Resch, Claudia, Schaeffeler, Elke, Rius, Maria, Schwab, Matthias
Format:	Online
Language:	English
Published:	Public Library of Science 2011
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3136501/

id	pubmed-3136501
recordtype	oai_dc
spelling	pubmed-31365012011-07-21 Proton Pump Inhibitors Inhibit Metformin Uptake by Organic Cation Transporters (OCTs) Nies, Anne T. Hofmann, Ute Resch, Claudia Schaeffeler, Elke Rius, Maria Schwab, Matthias Research Article Metformin, an oral insulin-sensitizing drug, is actively transported into cells by organic cation transporters (OCT) 1, 2, and 3 (encoded by SLC22A1, SLC22A2, or SLC22A3), which are tissue specifically expressed at significant levels in various organs such as liver, muscle, and kidney. Because metformin does not undergo hepatic metabolism, drug-drug interaction by inhibition of OCT transporters may be important. So far, comprehensive data on the interaction of proton pump inhibitors (PPIs) with OCTs are missing although PPIs are frequently used in metformin-treated patients. Using in silico modeling and computational analyses, we derived pharmacophore models indicating that PPIs (i.e. omeprazole, pantoprazole, lansoprazole, rabeprazole, and tenatoprazole) are potent OCT inhibitors. We then established stably transfected cell lines expressing the human uptake transporters OCT1, OCT2, or OCT3 and tested whether these PPIs inhibit OCT-mediated metformin uptake in vitro. All tested PPIs significantly inhibited metformin uptake by OCT1, OCT2, and OCT3 in a concentration-dependent manner. Half-maximal inhibitory concentration values (IC50) were in the low micromolar range (3–36 µM) and thereby in the range of IC50 values of other potent OCT drug inhibitors. Finally, we tested whether the PPIs are also transported by OCTs, but did not identify PPIs as OCT substrates. In conclusion, PPIs are potent inhibitors of the OCT-mediated metformin transport in vitro. Further studies are needed to elucidate the clinical relevance of this drug-drug interaction with potential consequences on metformin disposition and/or efficacy. Public Library of Science 2011-07-14 /pmc/articles/PMC3136501/ /pubmed/21779389 http://dx.doi.org/10.1371/journal.pone.0022163 Text en Nies et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Nies, Anne T. Hofmann, Ute Resch, Claudia Schaeffeler, Elke Rius, Maria Schwab, Matthias
spellingShingle	Nies, Anne T. Hofmann, Ute Resch, Claudia Schaeffeler, Elke Rius, Maria Schwab, Matthias Proton Pump Inhibitors Inhibit Metformin Uptake by Organic Cation Transporters (OCTs)
author_facet	Nies, Anne T. Hofmann, Ute Resch, Claudia Schaeffeler, Elke Rius, Maria Schwab, Matthias
author_sort	Nies, Anne T.
title	Proton Pump Inhibitors Inhibit Metformin Uptake by Organic Cation Transporters (OCTs)
title_short	Proton Pump Inhibitors Inhibit Metformin Uptake by Organic Cation Transporters (OCTs)
title_full	Proton Pump Inhibitors Inhibit Metformin Uptake by Organic Cation Transporters (OCTs)
title_fullStr	Proton Pump Inhibitors Inhibit Metformin Uptake by Organic Cation Transporters (OCTs)
title_full_unstemmed	Proton Pump Inhibitors Inhibit Metformin Uptake by Organic Cation Transporters (OCTs)
title_sort	proton pump inhibitors inhibit metformin uptake by organic cation transporters (octs)
description	Metformin, an oral insulin-sensitizing drug, is actively transported into cells by organic cation transporters (OCT) 1, 2, and 3 (encoded by SLC22A1, SLC22A2, or SLC22A3), which are tissue specifically expressed at significant levels in various organs such as liver, muscle, and kidney. Because metformin does not undergo hepatic metabolism, drug-drug interaction by inhibition of OCT transporters may be important. So far, comprehensive data on the interaction of proton pump inhibitors (PPIs) with OCTs are missing although PPIs are frequently used in metformin-treated patients. Using in silico modeling and computational analyses, we derived pharmacophore models indicating that PPIs (i.e. omeprazole, pantoprazole, lansoprazole, rabeprazole, and tenatoprazole) are potent OCT inhibitors. We then established stably transfected cell lines expressing the human uptake transporters OCT1, OCT2, or OCT3 and tested whether these PPIs inhibit OCT-mediated metformin uptake in vitro. All tested PPIs significantly inhibited metformin uptake by OCT1, OCT2, and OCT3 in a concentration-dependent manner. Half-maximal inhibitory concentration values (IC50) were in the low micromolar range (3–36 µM) and thereby in the range of IC50 values of other potent OCT drug inhibitors. Finally, we tested whether the PPIs are also transported by OCTs, but did not identify PPIs as OCT substrates. In conclusion, PPIs are potent inhibitors of the OCT-mediated metformin transport in vitro. Further studies are needed to elucidate the clinical relevance of this drug-drug interaction with potential consequences on metformin disposition and/or efficacy.
publisher	Public Library of Science
publishDate	2011
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3136501/
_version_	1611465591940448256

Proton Pump Inhibitors Inhibit Metformin Uptake by Organic Cation Transporters (OCTs)

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