Bio: Lucie Chevillard is an associate professor in pharmacokinetics and a researcher specializing in psychotropic drug toxicity within the Inserm UMRS-1144 unit. Her work focuses on opioid and psychoactive substance toxicity, lithium toxicity variability, and optimizing central analgesics. She combines clinical data, animal studies, and pharmacokinetic/pharmacodynamic modeling to improve therapeutic strategies. Her research has highlighted critical drug interactions, respiratory risks, and novel approaches to pain management. To date, she has authored numerous scientific publications, contributing to advancements in neuropsychopharmacology.

Abstract: Metformin, a biguanide, is the most prescribed first-line antidiabetic drug worldwide. Metformin-induced (MILA, following a massive ingestion) or metformin-associated lactic acidosis (MALA, due to the development of concomitant morbidity with acute kidney injury) are recognized adverse effects although disputed by some clinicians until recently. Metformin is responsible for an increase in lactate production in the intestine and a decrease in the liver gluconeogenesis leading to increased amounts of gluconeogenic substrates such as pyruvate and alanine. Inhibition of complex-I in the electron transport chain impairs the pyruvate metabolism to acetyl-CoA resulting in enhanced lactate production. Inappropriate recycling of protons produced by cellular metabolism results in proton leaks out of the mitochondria and metabolic acidosis. Additionally, both acidosis-related vasodilatation and myocardial contractility depression enhance lactate production. Interestingly, oxygen consumption was shown to be depressed in patients with lactic acidosis due to metformin toxicity. Similarly, Lower complex-I and complex-IV activities were found ex-vivo in platelets from metformin-poisoned patients compared to controls. This lecture will focus on the most recently published experimental data investigating the mechanisms of metformin-induced toxicity of the mitochondria and the development of possible therapeutics to reduce the resulting morbidities and mortality.