RATIONALE: 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.
OBJECTIVE: We sought to identify statin transporters in human skeletal muscle 
and determine their impact on statin toxicity in vitro.
METHODS AND RESULTS: 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.
CONCLUSIONS: These results identify key membrane transporters as modulators of 
skeletal muscle statin exposure and toxicity.