Abstract
Many drugs can cause unexpected muscle disorders, often necessitating the cessation of an effective medication. Inhibition of monocarboxylate transporters (MCTs) may potentially lead to perturbation of l-lactic acid homeostasis and muscular toxicity. Previous studies have shown that statins and loratadine have the potential to inhibit l-lactic acid efflux by MCTs (MCT1 and 4). The main objective of this study was to confirm the inhibitory potentials of atorvastatin, simvastatin (acid and lactone forms), rosuvastatin, and loratadine on l-lactic acid transport using primary human skeletal muscle cells (SkMC). Loratadine (IC50 31 and 15 µM) and atorvastatin (IC50 ~130 and 210 µM) demonstrated the greatest potency for inhibition of l-lactic acid efflux at pH 7.0 and 7.4, respectively (~2.5-fold l-lactic acid intracellular accumulation). Simvastatin acid exhibited weak inhibitory potency on l-lactic acid efflux with an intracellular lactic acid increase of 25–35%. No l-lactic acid efflux inhibition was observed for simvastatin lactone or rosuvastatin. Pretreatment studies showed no change in inhibitory potential and did not affect lactic acid transport for all tested drugs. In conclusion, we have demonstrated that loratadine and atorvastatin can inhibit the efflux transport of l-lactic acid in SkMC. Inhibition of l-lactic acid efflux may cause an accumulation of intracellular l-lactic acid leading to the reported drug-induced myotoxicity.
Highlights
Adverse drug reactions (ADRs) are an important public health problem
We demonstrated that some statins are able to inhibit the efflux of L-lactic acid via MCT1 and MCT4 in breast cancer cell lines (Hs578T selectively expressing MCT1 and MDA-MB-231 selectively expressing MCT4)
At pH 7.4, loratadine was a more potent monocarboxylate transporters (MCTs) inhibitor than atorvastatin on the L-lactic acid efllux, 2017, with9,IC
Summary
Adverse drug reactions (ADRs) are an important public health problem. Death caused by ADRs has increased over the years and, since 2011, has surpassed motor vehicle traffic-related injuries [1]. There are many factors that can contribute to this situation, such as polypharmacy in the aging population, drug-drug interactions, and interindividual genetic variability modulating the pharmacodynamics and pharmacokinetics of drugs inside the organism [2,3,4]. Many common medications can induce musculoskeletal disorders, while their incidence is still unclear due to the lack of clear definitions (e.g., under drug-drug interaction conditions). Drug-related musculoskeletal disorders have been reported more frequently since the introduction into the market of widely prescribed lipid lowering drugs, such as fibrates and statins [5]. Drug-induced myopathies can range from mild myalgias to myopathies with weakness and severe life-threatening rhabdomyolysis
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