{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T21:33:16Z","timestamp":1789421596062,"version":"build-2803163510"},"reference-count":28,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2012,5,8]],"date-time":"2012-05-08T00:00:00Z","timestamp":1336435200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2012,6]]},"abstract":"<jats:sec><jats:title>BACKGROUNDS AND PURPOSE<\/jats:title><jats:p>Lactic acidosis is a fatal adverse effect of metformin, but the risk factor remains unclear. Multidrug and toxin extrusion 1 (MATE1) is expressed in the luminal membrane of the kidney and liver. MATE1 was revealed to be responsible for the tubular and biliary secretion of metformin. Therefore, some <jats:italic>MATE<\/jats:italic> polymorphisms, that cause it to function abnormally, are hypothesized to induce lactic acidosis. The purpose of this study is to clarify the association between <jats:italic>MATE<\/jats:italic> dysfunction and metformin\u2010induced lactic acidosis.<\/jats:p><\/jats:sec><jats:sec><jats:title>EXPERIMENTAL APPROACH<\/jats:title><jats:p>Blood lactate, pH and bicarbonate ion (HCO<jats:sub>3<\/jats:sub><jats:sup>\u2010<\/jats:sup>) levels were evaluated during continuous administration of 3\u2003mg\u00b7mL<jats:sup>\u22121<\/jats:sup> metformin in drinking water using <jats:italic>Mate1<\/jats:italic> knockout (\u2212\/\u2212), heterozygous (+\/\u2212) and wild\u2010type (+\/+) mice. To determine the tissue accumulation of metformin, mice were given 400\u2003mg\u00b7kg<jats:sup>\u22121<\/jats:sup> metformin orally. Furthermore, blood lactate data were obtained from diabetic patients given metformin.<\/jats:p><\/jats:sec><jats:sec><jats:title>KEY RESULTS<\/jats:title><jats:p>Seven days after metformin administration in drinking water, significantly higher blood lactate, lower pH and HCO<jats:sub>3<\/jats:sub><jats:sup>\u2010<\/jats:sup> levels were observed in <jats:italic>Mate1<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice, but not in <jats:italic>Mate1<\/jats:italic><jats:sup>+\/\u2212<\/jats:sup> mice. The blood lactate levels were not affected in patients with the heterozygous <jats:italic>MATE<\/jats:italic> variant (<jats:italic>MATE1<\/jats:italic>\u2010L125F, <jats:italic>MATE1<\/jats:italic>\u2010G64D, <jats:italic>MATE2\u2010K<\/jats:italic>\u2010G211V). Sixty minutes after metformin administration (400\u2003mg\u00b7kg<jats:sup>\u22121<\/jats:sup>, p.o.) the hepatic concentration of metformin was markedly higher in <jats:italic>Mate1<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice than in <jats:italic>Mate1<\/jats:italic><jats:sup>+\/+<\/jats:sup> mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>CONCLUSION AND IMPLICATIONS<\/jats:title><jats:p>MATE1 dysfunction caused a marked elevation in the metformin concentration in the liver and led to lactic acidosis, suggesting that the homozygous <jats:italic>MATE1<\/jats:italic> variant could be one of the risk factors for metformin\u2010induced lactic acidosis.<\/jats:p><\/jats:sec>","DOI":"10.1111\/j.1476-5381.2012.01853.x","type":"journal-article","created":{"date-parts":[[2012,1,13]],"date-time":"2012-01-13T17:19:21Z","timestamp":1326475161000},"page":"1183-1191","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":75,"title":["Loss of multidrug and toxin extrusion 1 (MATE1) is associated with metformin\u2010induced lactic 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