What is the mechanism of metformin-induced lactic acidosis ?

Lactic acid, the product of anaerobic glycolysis, is primarily produced and is fully dissociated into lactate and protons in both extracellular and intracellular fluids. Several studies have reported a small but significant increase in lactic acid levels with metformin use, in particular after meals. Metformin raises lactic acid levels by affecting the redox potential and promoting anaerobic metabolism. It interferes with complex I of the respiratory chain, leading to an inhibition of mitochondrial respiration. In the presence of hypoxia or tissue hypoperfusion, it can block mitochondrial oxidative phosphorylation inhibiting adenosine triphosphate synthesis, leading to a decrease in the ATP:ADP ratio and an increase in the NADH:NAD ratio. This can result in an accumulation of pyruvate that is later converted into lactate. This conversion allows for the regeneration of NAD+, enabling the production of ATP by anaerobic glycolysis, a much less efficient pathway. Increasing evidence indicates genetic differences that may explain interindividual variation in clinical response as well as renal clearance and bioavailability of the drug. Drug transporters, including plasma membrane monoamine transporter, organic cation transporters and multidrug and toxin extrusion transporter 1, have been recognized to play a major role in the absorption, distribution and elimination of metformin.46,47 In animal models, it was recently reported that MATE-1 dysfunction can lead to lactic acidosis after metformin treatment

Metformin-associated lactic acidosis.” The American journal of the medical sciences 349.3 (2015):263-267.

Metformin is a safe drug when correctly used in properly selected patients. In real life, however, associated lactic acidosis has been repeatedly, although rarely, reported. The term metformin-induced lactic acidosis refers to cases that cannot be explained by any major risk factor other than drug accumulation, usually due to renal failure. Treatment consists of vital function support and drug removal, mainly achieved by renal replacement therapy. Despite dramatic clinical presentation, the prognosis of metformin-induced lactic acidosis is usually surprisingly good.

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