Statin-induced myopathy in the rat: relationship between systemic exposure, muscle exposure and myopathy.
Rare instances of myopathy are associated with all statins, but cerivastatin was withdrawn from clinical use due to a greater incidence of myopathy. The mechanism of statin-induced myopathy with respect to tissue disposition was investigated by measuring the systemic, hepatic, and skeletal muscle exposure of cerivastatin, rosuvastatin, and simvastatin in rats before and after muscle damage. The development of myopathy was not associated with the accumulation of statins in skeletal muscle. For each statin exposure was equivalent in muscles irrespective of their fibre-type sensitivity to myopathy. The low amount of each statin in skeletal muscle relative to the liver does not support a significant role for transporters in the disposition of statins in skeletal muscle. Finally, the concentration of cerivastatin necessary to cause necrosis in skeletal muscle was considerably lower than rosuvastatin or simvastatin, supporting the concept cerivastatin is intrinsically more myotoxic than other statins.
Sidaway
J
J
Safety Assessment, AstraZeneca, Alderley Park, Macclesfield, UK. james.sidaway@astrazeneca.com
Wang
Y
Y
Marsden
A M
AM
Orton
T C
TC
Westwood
F R
FR
Azuma
C T
CT
Scott
R C
RC
D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D005464:Fluorobenzenes / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity*; D008099:Liver / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism; D009135:Muscular Diseases / Q000097:blood / Q000139:chemically induced*; D011725:Pyridines / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity; D011743:Pyrimidines / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D000068718:Rosuvastatin Calcium; D019821:Simvastatin / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity; D013449:Sulfonamides / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity
D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; D013449:Sulfonamides; D000068718:Rosuvastatin Calcium; D019821:Simvastatin; C086276:cerivastatin