title: Metformin induces lactate production in peripheral blood mononuclear cells and platelets through specific mitochondrial complex I inhibition.
abstract: OBJECTIVE
  Metformin is a widely used antidiabetic drug associated with the rare side effect of lactic acidosis which has been proposed to be linked to drug-induced mitochondrial dysfunction. Using respirometry, the aim of this study was to evaluate mitochondrial toxicity of metformin to human blood cells in relation to that of phenformin, a biguanide analogue withdrawn in most countries due to a high incidence of lactic acidosis.
  
  
  METHODS
  Peripheral blood mononuclear cells and platelets were isolated from healthy volunteers, and integrated mitochondrial function was studied in permeabilized and intact cells using high-resolution respirometry. A wide concentration range of metformin (0.1-100 mm) and phenformin (25-500 μm) was investigated for dose- and time-dependent effects on respiratory capacities, lactate production and pH.
  
  
  RESULTS
  Metformin induced respiratory inhibition at complex I in peripheral blood mononuclear cells and platelets (IC50 0.45 mm and 1.2 mm respectively). Phenformin was about 20-fold more potent in complex I inhibition of platelets than metformin. Metformin further demonstrated a dose- and time-dependent respiratory inhibition and augmented lactate release at a concentration of 1 mm and higher.
  
  
  CONCLUSIONS
  Respirometry of human peripheral blood cells readily detected respiratory inhibition by metformin and phenformin specific to complex I, providing a suitable model for probing drug toxicity. Lactate production was increased at concentrations relevant for clinical metformin intoxication, indicating mitochondrial inhibition as a direct causative pathophysiological mechanism. Relative to clinical dosing, phenformin displayed a more potent respiratory inhibition than metformin, possibly explaining the higher incidence of lactic acidosis in phenformin-treated patients.
authors.affiliation: Mitochondrial Medicine, Department of Clinical Sciences, Lund University, Lund, Sweden; NeuroVive Pharmaceutical AB, Lund, Sweden.
authors.forename: S
authors.initials: S
authors.lastname: Piel
authors.forename: J K
authors.initials: JK
authors.lastname: Ehinger
authors.forename: E
authors.initials: E
authors.lastname: Elmér
authors.forename: M J
authors.initials: MJ
authors.lastname: Hansson
mesh_terms: D001792:Blood Platelets / Q000187:drug effects*; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D019344:Lactic Acid / Q000097:blood*; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects*; D010101:Oxygen Consumption / Q000187:drug effects
chemical_list: D007004:Hypoglycemic Agents; D019344:Lactic Acid; D008687:Metformin
keywords: drug screening; human; metformin; mitochondrial toxicity; phenformin; respirometry