Inhibition of the lactic acid transporters MCT1 and MCT4 as an underlying mechanism for drug-induced myopathy

Drug-induced myopathy is a serious side effect caused by various widely-administered medications. These muscle-related symptoms range from mild myalgia with or without creatine kinase increase, muscle weakness, myositis, to rare life-threatening rhabdomyolysis. While mild myalgias can be tolerable, chronic myopathies can affect the patients' quality of life, frequently requiring the cessation of an effective drug.  The underlying mechanism of these drug-induced myotoxicities is known for some drugs but remains unclear for most (e.g. statins). Statins constitute an effective cholesterol-lowering therapy, but they are known to cause these adverse drug reactions. Various factors increasing statin plasma levels (e.g. high doses, drug-drug interactions, genetic polymorphisms) seem to be linked with a higher occurrence of myotoxicity. Consequently, systemic drug metabolism and transport, controlling overall absorption, distribution and elimination, can become important. However, these factors only partly explain the observed muscular disorders.  Although there are several proposed mechanisms for statin-induced myotoxicity, the exact mechanism responsible for this effect is still debated with studies reporting conflicting results. Since exercise seems to exacerbate muscle pain in patients under statin treatment, the premise of this project is that L-lactic acid transport via the monocarboxylate transporters is involved in the development of drug-induced myopathy. Since lactic acid is one of the major byproducts resulting from physical activity, its efficient removal from the muscle cells is essential. Therefore, the administration of drugs competitively inhibiting those transporters may potentially lead to perturbation of L-lactic acid homeostasis and muscular disorders.  The aim of the first part of this study was to assess the inhibitory potential of acidic drugs on L-lactic acid transport using breast cancer cell lines Hs578T and MDA-MB-231, which selectively express MCT1 or MCT4, respectively. These cell lines allowed transporter characterization with the determination of their kinetic parameters and inhibition. The main objective of the second part of this study was to confirm the inhibitory potentials of atorvastatin, simvastatin, rosuvastatin and loratadine on L-lactic acid transport in a more physiological setting using primary human skeletal muscle cells (SkMC). The overall goal of this doctoral project was to better understand the mechanisms behind certain drug-induced myopathies, more specifically those induced by statins and loratadine, by studying monocarboxylate transporters involved in lactic acid transport and pH homeostasis in the muscle.  Loratadine and atorvastatin demonstrated the greatest potency for inhibition of L-lactic acid efflux first in cancer cell lines, an observation confirmed in SkMC. This inhibition may cause an accumulation of intracellular L-lactic acid leading to acidification and muscular disorders.  Further studies with in vivo models are required to confirm the physiological impact of our findings in a clinical setting. These data will help understand statin- and loratadine-induced myopathy and prevent its occurrence by optimizing treatment strategies.

Keyphrases: Muscle, Loratadine, Lactic acid, Monocarboxylate transporters, Statins, Drug transporters, Drug-induced myopathy, Muscle, Adverse events, Loratadine, Cholesterol