Effects of HMG-CoA reductase inhibitors on skeletal muscles of rabbits.
This study was undertaken to evaluate the potential of HMG-CoA reductase inhibitors, pravastatin sodium (hereafter abbreviated to pravastatin) and simvastatin, for induction of myopathy and influence on the ubiquinone content of skeletal and cardiac muscles and other tissues in the rabbit. Both drugs were administered orally to New Zealand White rabbits (n = 5) at the dose of 50 mg/kg per day for 14 days. Serum cholesterol levels in the pravastatin- and simvastatin-treated groups were reduced significantly by 47% an 58% on day 14 (P < 0.05), respectively, as compared with the control group, but the difference between the two treatment groups was not significant. In animals of the simvastatin-treated group, abnormal elevations of creatine kinase (CK) and lactate dehydrogenase (LDH) levels were observed, in association with severe lesions in skeletal muscles, but not cardiac muscle. The ubiquinone content in skeletal muscle in this treatment group was not affected, even in the muscles that had severe lesions, whereas that in liver and cardiac muscle was significantly reduced compared with the control group. The results suggest that there is no direct correlation between myopathy and the decrease of ubiquinone content in skeletal muscles. In contrast, the animals in the pravastatin-treated group did not show any changes in CK and LDH levels, ubiquinone content in liver and muscles, or in histopathological features of muscle fibers. The difference between the adverse effects seen with the two drugs could be attributed to physicochemical properties: simvastatin permeates the plasma membrane because of its hydrophobic nature, whereas pravastatin does not, because it is hydrophilic.
Fukami
M
M
Biological Research Laboratories, Sankyo Co., Ltd., Tokyo, Japan.
Maeda
N
N
Fukushige
J
J
Kogure
Y
Y
Shimada
Y
Y
Ogawa
T
T
Tsujita
Y
Y
D000284:Administration, Oral; D000818:Animals; D002784:Cholesterol / Q000097:blood; D003402:Creatine Kinase / Q000097:blood; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008148:Lovastatin / Q000031:analogs & derivatives* / Q000633:toxicity; D008297:Male; D009132:Muscles / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009135:Muscular Diseases / Q000139:chemically induced / Q000473:pathology; D017035:Pravastatin / Q000633:toxicity*; D011817:Rabbits; D019821:Simvastatin; D014451:Ubiquinone / Q000378:metabolism
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D014451:Ubiquinone; D002784:Cholesterol; D008148:Lovastatin; D019821:Simvastatin; D007770:L-Lactate Dehydrogenase; D003402:Creatine Kinase; D017035:Pravastatin