Human skeletal muscle drug transporters determine local exposure and toxicity of statins.
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Knauer MJ, Urquhart BL, Meyer zu Schwabedissen HE, Schwarz UI, Lemke CJ, Leake BF, Kim RB, Tirona RG
Human skeletal muscle drug transporters determine local exposure and toxicity of statins.
Circ Res. 2010 Feb 5;106(2):297-306. doi: 10.1161/CIRCRESAHA.109.203596. Epub 2009 Nov 25.
- PubMed ID
- 19940267 [ View in PubMed]
- Abstract
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.
DrugBank Data that Cites this Article
- Drug Transporters
Drug Transporter Kind Organism Pharmacological Action Actions Atorvastatin Multidrug resistance-associated protein 1 Protein Humans NoSubstrateDetails Atorvastatin Multidrug resistance-associated protein 4 Protein Humans NoSubstrateDetails Atorvastatin Multidrug resistance-associated protein 5 Protein Humans NoSubstrateDetails Atorvastatin Solute carrier organic anion transporter family member 2B1 Protein Humans NoSubstrateDetails Rosuvastatin Multidrug resistance-associated protein 4 Protein Humans UnknownSubstrateDetails