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ToxSci Advance Access published online on September 1, 2005
Toxicological Sciences, doi:10.1093/toxsci/kfi305
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© The Author 2005. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org
Received July 5, 2005
Accepted August 25, 2005

Safety Evaluation

Roles of Exercise and Pharmacokinetics in Cerivastatin-Induced Skeletal Muscle Toxicity

Jennifer L. Seachrist 1*, Cho-Ming Loi 2, Mark G. Evans 1, Kay A. Criswell 1, and Charles E. Rothwell 1

1 Safety Sciences Department, Pfizer Global Research & Development, 2800 Plymouth Road, Ann Arbor, MI 48105
2 Pharmacokinetics, Dynamics and Metabolism Department, Pfizer Global Research & Development, 2800 Plymouth Road, Ann Arbor, MI 48105

* To whom correspondence should be addressed.
Jennifer L. Seachrist, E-mail: Jennifer.Seachrist{at}Pfizer.com


  Abstract

Three-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors are associated with adverse skeletal muscle effects, but the underlying mechanisms remain unclear. To determine whether toxicity involves the level of drug exposure in muscle tissue and to test the effect of exercise on cerivastatin (CVA)-induced skeletal muscle damage, female rats were administered vehicle or CVA at 0.1, 0.5 and 1.0 mg/kg/day by gavage for 2 weeks and exercised or not on treadmills for 20 min/day. Clinical chemistry and plasma and tissue pharmacokinetics were evaluated; light and transmission electron microscopy (TEM) of Type I and Type II fiber-predominant skeletal muscles were performed. Serum levels of AST, ALT, CK and plasma lactic acid were significantly elevated dose-dependently. CVA treatment decreased psoas and quadriceps weights. At 1 mg/kg all muscles except soleus demonstrated degeneration. Exercise-exacerbated severity of CVA-induced degeneration was evident in all muscles sampled except soleus and quadriceps. Early mitochondrial involvement in toxicity is suggested by the numerous membranous whorls and degenerate mitochondria observed in muscles at 0.5 mg/kg. No significant differences in CVA concentrations between either EDL and soleus or plasma and muscle were found. We found that CVA had no effect on cleaved caspase 3. In summary, we found that treadmill exercise exacerbated the incidence and severity of CVA-induced damage in Type II fiber-predominant muscles. Tissue exposure is likely not the key factor mediating CVA-induced skeletal muscle toxicity.

Keywords: pharmacokinetics; ultrastructure; muscle weight; degeneration; treadmill; statins.
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