Differential effects of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors on the development of myopathy in young rats.
HMG-CoA reductase inhibitors (statins), cholesterol-lowering drugs that have not been approved for use in children and adolescents, may cause myopathy as a side effect. We compared the effects of three statins (simva-, prava- and lovastatin) in young rats to determine whether skeletal muscle of young animals is more susceptible than that of adults. We also evaluated whether the type of statin (lipophilic versus hydrophilic) determines the degree of muscle damage. Administration via chow of simvastatin (15 mg/kg of body weight/d) and lovastatin (43-55 mg/kg of body weight/d), both lipophilic, caused stunted growth, high creatine kinase (CK) activity in plasma, and severe myopathy. Statin doses that caused damage were much lower for young rats than for adults. Pravastatin (8-55 mg/kg of body weight/d), a hydrophilic drug, caused none of these symptoms. Histologic analysis of hind paw muscles of simvastatin-and lovastatin-treated rats showed abundant signs of damage (hypercontraction, fiber necrosis) in the extensor digitorum longus, correlating with the symptoms noted above. No cellular infiltrates were seen at the onset, pointing to a noninflammatory myopathy. Pravastatin-treated rats never showed signs of myopathy. Impaired DNA synthesis may explain why muscle toxicity is seen at lower doses in young, rapidly developing rats than in adult animals. The differences in muscle damage between the statins may be attributed to differences in lipophilicity and thus in tissue selectivity. Our results can be important when considering drug therapy in young patients with inherited lipoprotein disorders.
Reijneveld
J C
JC
Department of Neurology, Medical School Utrecht University, The Netherlands.
Koot
R W
RW
Bredman
J J
JJ
Joles
J A
JA
Bär
P R
PR
D000818:Animals; D003402:Creatine Kinase / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008148:Lovastatin / Q000494:pharmacology*; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects / Q000473:pathology; D017035:Pravastatin / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
D004791:Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008148:Lovastatin; D003402:Creatine Kinase; D017035:Pravastatin