Human skeletal muscle drug transporters determine local exposure and toxicity of statins.
BACKGROUND
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.


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.
Knauer
Michael J
MJ
Department of Physiology & Pharmacology, Department of Medicine, University of Western Ontario, London, Canada.
Urquhart
Bradley L
BL
Meyer zu Schwabedissen
Henriette E
HE
Schwarz
Ute I
UI
Lemke
Christopher J
CJ
Leake
Brenda F
BF
Kim
Richard B
RB
Tirona
Rommel G
RG
D000069059:Atorvastatin; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D005464:Fluorobenzenes / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D020869:Gene Expression Profiling; D006367:HeLa Cells; D006538:Heptanoic Acids / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D015151:Immunoblotting; D007150:Immunohistochemistry; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism*; D032446:Myoblasts / Q000166:cytology / Q000378:metabolism*; D027361:Organic Anion Transporters / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D011758:Pyrroles / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology
D000069059:Atorvastatin; D005464:Fluorobenzenes; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D027361:Organic Anion Transporters; D011743:Pyrimidines; D011758:Pyrroles; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides; C073492:ABCC4 protein, human; C120809:ABCC5 protein, human; C450859:SLCO2B1 protein, human; C421109:multidrug resistance-associated protein 1