Rosuvastatin: characterization of induced myopathy in the rat.
Rosuvastatin is a relatively new member of the statin family (HMG-CoA reductase inhibitors), with superior lipid-lowering effects and a pattern of clinical side effects, including a low incidence of myopathy, similar to other widely prescribed statins. This article describes investigations of myopathy in the rat following administration of very high doses of rosuvastatin. The nature of the changes were found to be entirely consistent with those seen with other statins, including a differential sensitivity of muscle fibers (with glycolytic fibers [type IIB] the most sensitive and oxidative fibers [type I] the least), a delay of approximately 10 days after the start of oral dosing before necrosis was apparent, and ultrastructural alterations appearing first in mitochondria. In addition, the development of myopathy was prevented by coadministration of mevalonate, the product of HMG-CoA reductase. The findings illustrate a pattern of induced myopathy in the rat directly attributable to inhibition of HMG-CoA reductase that is entirely consistent between the various statins, with the oral dose required to produce the changes being a differentiating feature (based on these new data and a previously reported study from the same laboratory): cerivastatin dose less than simvastatin, and simvastatin dose less than rosuvastatin.
Westwood
F Russell
FR
Global Safety Assessment, AstraZeneca, Mereside, Alderley Park Macclesfield, Cheshire, SK10 4TG, United Kingdom. russell.westwood@astrazeneca.com
Scott
Robert C
RC
Marsden
Alan M
AM
Bigley
Alison
A
Randall
Kevin
K
D000284:Administration, Oral; D000818:Animals; D015415:Biomarkers / Q000032:analysis; D001835:Body Weight / Q000187:drug effects; D003402:Creatine Kinase / Q000097:blood; D004305:Dose-Response Relationship, Drug; D005260:Female; D005464:Fluorobenzenes / Q000633:toxicity*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000633:toxicity*; D018656:Muscle Fibers, Fast-Twitch / Q000187:drug effects / Q000648:ultrastructure; D018657:Muscle Fibers, Slow-Twitch / Q000187:drug effects / Q000648:ultrastructure; D018482:Muscle, Skeletal / Q000737:chemistry / Q000187:drug effects* / Q000473:pathology; D009135:Muscular Diseases / Q000097:blood / Q000139:chemically induced* / Q000473:pathology; D009336:Necrosis; D011743:Pyrimidines / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000633:toxicity*; D013997:Time Factors
D015415:Biomarkers; D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; D000068718:Rosuvastatin Calcium; D003402:Creatine Kinase