Department of Physiology & Pharmacology, Department of Medicine, University of Western Ontario, London, Canada.
Circ Res. 2010 Feb 5;106(2):297-306. doi: 10.1161/CIRCRESAHA.109.203596. Epub 2009 Nov 25.
The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or statins, are important drugs used in the treatment and prevention of cardiovascular disease. Although statins are well tolerated, many patients develop myopathy manifesting as muscle aches and pain. Rhabdomyolysis is a rare but severe toxicity of statins. Interindividual differences in the activities of hepatic membrane drug transporters and metabolic enzymes are known to influence statin plasma pharmacokinetics and risk for myopathy. Interestingly, little is known regarding the molecular determinants of statin distribution into skeletal muscle and its relevance to toxicity.
We sought to identify statin transporters in human skeletal muscle and determine their impact on statin toxicity in vitro.
We demonstrate that the uptake transporter OATP2B1 (human organic anion transporting polypeptide 2B1) and the efflux transporters, multidrug resistance-associated protein (MRP)1, MRP4, and MRP5 are expressed on the sarcolemmal membrane of human skeletal muscle fibers and that atorvastatin and rosuvastatin are substrates of these transporters when assessed using a heterologous expression system. In an in vitro model of differentiated, primary human skeletal muscle myoblast cells, we demonstrate basal membrane expression and drug efflux activity of MRP1, which contributes to reducing intracellular statin accumulation. Furthermore, we show that expression of human OATP2B1 in human skeletal muscle myoblast cells by adenoviral vectors increases intracellular accumulation and toxicity of statins and such effects were abrogated when cells overexpressed MRP1.
These results identify key membrane transporters as modulators of skeletal muscle statin exposure and toxicity.
3-羟基-3-甲基戊二酰辅酶 A 还原酶抑制剂，即他汀类药物，是治疗和预防心血管疾病的重要药物。虽然他汀类药物耐受性良好，但许多患者会出现表现为肌肉疼痛的肌病。横纹肌溶解症是他汀类药物罕见但严重的毒性。已知肝细胞膜药物转运体和代谢酶的个体差异会影响他汀类药物的血浆药代动力学和肌病风险。有趣的是，对于他汀类药物在骨骼肌中的分布及其与毒性的相关性的分子决定因素知之甚少。
我们旨在鉴定人骨骼肌中的他汀类药物转运体，并确定其对他汀类药物体外毒性的影响。
我们证明了摄取转运体 OATP2B1（人有机阴离子转运多肽 2B1）和外排转运体多药耐药相关蛋白 1（MRP1）、MRP4 和 MRP5 在人骨骼肌纤维的肌膜上表达，阿托伐他汀和瑞舒伐他汀在使用异源表达系统评估时是这些转运体的底物。在分化的原代人骨骼肌成肌细胞的体外模型中，我们证明了 MRP1 的基底膜表达和药物外排活性，这有助于减少细胞内他汀类药物的积累。此外，我们表明，通过腺病毒载体在人骨骼肌成肌细胞中表达人 OATP2B1 会增加他汀类药物的细胞内积累和毒性，而当细胞过度表达 MRP1 时，这种作用会被消除。
这些结果确定了关键的膜转运体作为调节骨骼肌他汀类药物暴露和毒性的调节剂。
