Role of multi-drug resistance-associated protein-1 transporter in statin-induced myopathy.
This study investigated the effects of probenecid to inhibit the multi-drug resistance-associated protein-1 (MRP-1) in mediating the efflux and myotoxicity in rat skeletal muscles, with administration of rosuvastatin. Male Sprague-Dawley rats were administered daily, for 15 days, with either rosuvastatin (50, 100 or 200 mg/kg) or probenecid (100 mg/kg) alone, or with a combination of rosuvastatin (50, 100 or 200 mg/kg) and probenecid (100 mg/kg). Skeletal muscle toxicity was elevated with probenecid administered with 200 mg/kg/day of rosuvastatin, with the elevation of creatine kinase by 12-fold, alanine aminotrasferase by 10-fold and creatinine by 9-fold at day 15, with no adverse effects observed when probenecid was given alone. Mitochondria ultrastructural damage with enlargement, disruption, cristolysis and vaculation was seen in the soleus and plantaris of animals administered with probenecid and high dosages of statin. These muscles were also expressing more succinic dehydrogenase (SDH)-positive and cytochrome oxidase (CyOX)-positive fibers. Although generally well-tolerated, statins produce a variety of adverse skeletal muscle events. Hydrophilic statins, with reduced levels of non-specific passive diffusion rates into extra-hepatic tissues, are still seen to produce myopathy. This highlights the important roles of transport mechanisms in statin transport at the skeletal muscles. Excessive influx, reduced efflux or the combination of the two could result in elevated cellular levels of statins at the skeletal muscles, resulting in toxicity. This study provides preliminary evidence that the MRP-1 transporter and efflux at skeletal muscles possibly play significant roles in statin-induced myopathy.
Dorajoo
Rajkumar s o
Rs
Pharmacogenetics Laboratory, Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Pereira
Barry P
BP
Yu
Zou
Z
Gopalakrishnakone
P
P
Leong
Cheng Chee
CC
Wee
Aileen
A
Lee
Edmund
E
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003576:Electron Transport Complex IV / Q000378:metabolism; D005464:Fluorobenzenes / Q000633:toxicity*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000633:toxicity*; D008297:Male; D046529:Microscopy, Electron, Transmission; D008931:Mitochondria, Muscle / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics* / Q000378:metabolism*; D018908:Muscle Weakness / Q000139:chemically induced / Q000503:physiopathology; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009135:Muscular Diseases / Q000139:chemically induced* / Q000235:genetics* / Q000378:metabolism; D016612:Paraffin Embedding; D011339:Probenecid / Q000494:pharmacology; D011743:Pyrimidines / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012076:Renal Agents / Q000494:pharmacology; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000633:toxicity*
D003576:Electron Transport Complex IV; D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011339:Probenecid; D011743:Pyrimidines; D012076:Renal Agents; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides; C421109:multidrug resistance-associated protein 1