Loss of multidrug and toxin extrusion 1 (MATE1) is associated with metformin-induced lactic acidosis

K. Toyama, A. Yonezawa, Satohiro Masuda, R. Osawa, M. Hosokawa, S. Fujimoto, N. Inagaki, K. Inui, T. Katsura

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Abstract

BACKGROUNDS AND PURPOSE 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 MATE polymorphisms, that cause it to function abnormally, are hypothesized to induce lactic acidosis. The purpose of this study is to clarify the association between MATE dysfunction and metformin-induced lactic acidosis. EXPERIMENTAL APPROACH Blood lactate, pH and bicarbonate ion (HCO 3 -) levels were evaluated during continuous administration of 3 mg·mL -1 metformin in drinking water using Mate1 knockout (-/-), heterozygous (+/-) and wild-type (+/+) mice. To determine the tissue accumulation of metformin, mice were given 400 mg·kg -1 metformin orally. Furthermore, blood lactate data were obtained from diabetic patients given metformin. KEY RESULTS Seven days after metformin administration in drinking water, significantly higher blood lactate, lower pH and HCO 3 - levels were observed in Mate1 -/- mice, but not in Mate1 +/- mice. The blood lactate levels were not affected in patients with the heterozygous MATE variant (MATE1-L125F, MATE1-G64D, MATE2-K-G211V). Sixty minutes after metformin administration (400 mg·kg -1, p.o.) the hepatic concentration of metformin was markedly higher in Mate1 -/- mice than in Mate1 +/+ mice. CONCLUSION AND IMPLICATIONS MATE1 dysfunction caused a marked elevation in the metformin concentration in the liver and led to lactic acidosis, suggesting that the homozygous MATE1 variant could be one of the risk factors for metformin-induced lactic acidosis.

Original languageEnglish
Pages (from-to)1183-1191
Number of pages9
JournalBritish Journal of Pharmacology
Volume166
Issue number3
DOIs
Publication statusPublished - Jun 1 2012

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All Science Journal Classification (ASJC) codes

  • Pharmacology

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Toyama, K., Yonezawa, A., Masuda, S., Osawa, R., Hosokawa, M., Fujimoto, S., ... Katsura, T. (2012). Loss of multidrug and toxin extrusion 1 (MATE1) is associated with metformin-induced lactic acidosis. British Journal of Pharmacology, 166(3), 1183-1191. https://doi.org/10.1111/j.1476-5381.2012.01853.x