title: Loss of multidrug and toxin extrusion 1 (MATE1) is associated with metformin-induced lactic acidosis.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Toyama
authors.forename: A
authors.initials: A
authors.lastname: Yonezawa
authors.forename: S
authors.initials: S
authors.lastname: Masuda
authors.forename: R
authors.initials: R
authors.lastname: Osawa
authors.forename: M
authors.initials: M
authors.lastname: Hosokawa
authors.forename: S
authors.initials: S
authors.lastname: Fujimoto
authors.forename: N
authors.initials: N
authors.lastname: Inagaki
authors.forename: K
authors.initials: K
authors.lastname: Inui
authors.forename: T
authors.initials: T
authors.lastname: Katsura
mesh_terms: D000140:Acidosis, Lactic / Q000097:blood / Q000139:chemically induced* / Q000378:metabolism; D000818:Animals; D003920:Diabetes Mellitus / Q000097:blood / Q000188:drug therapy; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006720:Homozygote; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D007677:Kidney Function Tests; D019344:Lactic Acid / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008111:Liver Function Tests; D008687:Metformin / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D027701:Organic Cation Transport Proteins / Q000235:genetics*; D013045:Species Specificity; D014162:Transfection
chemical_list: D007004:Hypoglycemic Agents; C514424:MATE1 protein, mouse; D027701:Organic Cation Transport Proteins; C521869:SLC47A1 protein, human; D019344:Lactic Acid; D008687:Metformin