Leung Yat Hei, Turgeon Jacques, Michaud Veronique
Faculty of Pharmacy, Université de Montréal, Montreal, QC H2X 0A9, Canada.
Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, QC H2X 0A9, Canada.
Pharmaceutics. 2017 Oct 10;9(4):42. doi: 10.3390/pharmaceutics9040042.
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 (IC 31 and 15 µM) and atorvastatin (IC 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.
许多药物可引发意想不到的肌肉疾病，常常需要停用有效的药物。单羧酸转运体（MCTs）受到抑制可能会扰乱L-乳酸的体内平衡并导致肌肉毒性。先前的研究表明，他汀类药物和氯雷他定有可能抑制MCTs（MCT1和4）介导的L-乳酸外排。本研究的主要目的是使用原代人骨骼肌细胞（SkMC）来确认阿托伐他汀、辛伐他汀（酸型和内酯型）、瑞舒伐他汀和氯雷他定对L-乳酸转运的抑制潜力。氯雷他定（IC 31和15 μM）和阿托伐他汀（IC ~130和210 μM）分别在pH 7.0和7.4时对L-乳酸外排表现出最强的抑制效力（L-乳酸细胞内蓄积增加约2.5倍）。辛伐他汀酸对L-乳酸外排的抑制效力较弱，细胞内乳酸增加25 - 35%。未观察到辛伐他汀内酯或瑞舒伐他汀对L-乳酸外排的抑制作用。预处理研究表明，所有受试药物的抑制潜力均无变化，且不影响乳酸转运。总之，我们已经证明氯雷他定和阿托伐他汀能够抑制SkMC中L-乳酸的外排转运。抑制L-乳酸外排可能会导致细胞内L-乳酸蓄积，进而引发所报道的药物诱导的肌毒性。
