• S Piel, J K Ehinger, E Elmér, and M J Hansson.
• Mitochondrial Medicine, Department of Clinical Sciences, Lund University, Lund, Sweden; NeuroVive Pharmaceutical AB, Lund, Sweden.
• Acta Physiol (Oxf). 2015 Jan 1;213(1):171-80.

AimMetformin 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mitochondrial toxicity of metformin to human blood cells in relation to that of phenformin, a biguanide analogue withdrawn in most countries due to a high incidence of lactic acidosis.MethodsPeripheral blood mononuclear cells and platelets were isolated from healthy volunteers, and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.ResultsMetformin 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.ConclusionRespirometry 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.© 2014 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.

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