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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Autores principales:	Anne T Nies, Ute Hofmann, Claudia Resch, Elke Schaeffeler, Maria Rius, Matthias Schwab
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/44451f338d6647e398dc36b6adfa052e
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spelling	oai:doaj.org-article:44451f338d6647e398dc36b6adfa052e2021-11-18T06:50:15ZProton pump inhibitors inhibit metformin uptake by organic cation transporters (OCTs).1932-620310.1371/journal.pone.0022163https://doaj.org/article/44451f338d6647e398dc36b6adfa052e2011-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21779389/?tool=EBIhttps://doaj.org/toc/1932-6203Metformin, 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 (IC(50)) were in the low micromolar range (3-36 µM) and thereby in the range of IC(50) 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.Anne T NiesUte HofmannClaudia ReschElke SchaeffelerMaria RiusMatthias SchwabPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 7, p e22163 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Anne T Nies Ute Hofmann Claudia Resch Elke Schaeffeler Maria Rius Matthias Schwab 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 (IC(50)) were in the low micromolar range (3-36 µM) and thereby in the range of IC(50) 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.
format	article
author	Anne T Nies Ute Hofmann Claudia Resch Elke Schaeffeler Maria Rius Matthias Schwab
author_facet	Anne T Nies Ute Hofmann Claudia Resch Elke Schaeffeler Maria Rius Matthias Schwab
author_sort	Anne T Nies
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).
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/44451f338d6647e398dc36b6adfa052e
work_keys_str_mv	AT annetnies protonpumpinhibitorsinhibitmetforminuptakebyorganiccationtransportersocts AT utehofmann protonpumpinhibitorsinhibitmetforminuptakebyorganiccationtransportersocts AT claudiaresch protonpumpinhibitorsinhibitmetforminuptakebyorganiccationtransportersocts AT elkeschaeffeler protonpumpinhibitorsinhibitmetforminuptakebyorganiccationtransportersocts AT mariarius protonpumpinhibitorsinhibitmetforminuptakebyorganiccationtransportersocts AT matthiasschwab protonpumpinhibitorsinhibitmetforminuptakebyorganiccationtransportersocts
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Proton pump inhibitors inhibit metformin uptake by organic cation transporters (OCTs).

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