DIFFERENTIAL-EFFECTS OF 3-HYDROXY-3-METHYLGLUTAYL-COENZYME-A REDUCTASE INHIBITORS ON THE DEVELOPMENT OF MYOPATHY IN YOUNG-RATS

HMG-CoA reductase inhibitors (statins), cholesterol-lowering drugs tha t have not been approved for use in children and adolescents, may caus e myopathy as a side effect. We compared the effects of three statins (simva-, prava- and lovastatin) in young rats to determine whether ske letal muscle of young animals is more susceptible than that of adults. We also evaluated whether the type of statin (lipophilic versus hydro philic) determines the degree of muscle damage. Administration via cho w of simvastatin (1.5 mg/kg of body weight/d) and lovastatin (43-55 mg /kg of body weight/d), both lipophilic, caused stunted growth, high cr eatine kinase (CK) activity in plasma, and severe myopathy. Statin dos es 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 sim vastatin- and lovastatin-treated rats showed abundant signs of damage (hypercontraction, fiber necrosis) in the extensor digitorum longus, c orrelating with the symptoms noted above. No cellular infiltrates were seen at the onset, pointing to a noninflammatory myopathy. Pravastati n-treated rats never showed signs of myopathy. Impaired DNA synthesis may explain why muscle toxicity is seen at lower doses in young, rapid ly developing rats than in adults animals. The difference in muscle da mage between the statins may be attributed to differences in lipophili city and thus in tissue selectivity. Our results can be important when considering drug therapy in young patients with inherited lipoprotein disorders.