|
Sign In to gain access to subscriptions and/or personal tools.
|
Subchronic Toxicity of Atorvastatin, a Hydroxymethylglutaryl-Coenzyme A Reductase Inhibitor, in Beagle Dogs
Kathleen M. Walsh
Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, Michigan 48105
Mudher A. Albassam
Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, Michigan 48105
David E. Clarke
Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, Michigan 48105
The toxicity of atorvastatin (AT), an inhibitor of hydroxymethylglutaryl-coenzyme A reductase (HMG), was evaluated in beagle dogs. In 4 studies [2-wk rising dose (daily increasing doses for 1 wk; maintenance for 1 wk), 12-wk rising dose (daily dosing with weekly increases in dose), 2-wk toxicity (daily dosing for 2 wk; 3 dose levels), 13-wk toxicity (daily dosing for 13 wk; 3 dose levels)], dogs received up to 400 mg/kg orally. Doses of 180 mg/kg induced moribundity, necessitating euthanasia. Weight losses up to 26% were seen at doses  150 mg/kg. Decreases in cholesterol levels were dose-related. Alanine and/or aspartate aminotransferase were increased at doses 80 mg/kg; alkaline phosphatase was increased at doses 150 mg/kg. Histopathologic findings were seen at 150 mg/kg and included hepatocellular eosinophilia related to increased smooth endoplasmic reticulum and cholangiohepatitis and cholecystitis at 150 mg/kg in the 2-wk toxicity study; hepatocellular degeneration, centrilobular bridging, cholecystitis, hemorrhage in gallbladder and brain, demyelination of optic nerve, and skeletal muscle necrosis at 280 mg/kg in the 12-wk rising dose study; and erosion and hemorrhage in large intestine, hepatocellular degeneration and necrosis, and inflammation and necrosis of gallbladder epithelium at 320 mg/kg in the 2-wk rising dose study. Doses up to 80 mg/kg for 13 wk did not induce histopathologic lesions in examined organs. AT effectively lowered serum cholesterol in normal lipidemic dogs. Toxicity of AT in dogs was similar to that with other inhibitors of HMG except that lenticular changes were not seen, significant hepatic, testicular, or neurological toxicity was associated only with high doses of AT, and skeletal muscle changes similar to those described in rats and rabbits were identified.
Key Words: Lipid regulation • liver • skeletal muscle • brain • cholesterol
Toxicologic Pathology, Vol. 24, No. 4,
468-476 (1996)
DOI: 10.1177/019262339602400409
 CiteULike  Complore  Connotea  Del.icio.us  Digg  Reddit  Technorati  Twitter What's this?
This article has been cited by other articles:
|
|
|
|
 
C. S. Madsen, E. Janovitz, R. Zhang, Van Nguyen-Tran, C. S. Ryan, X. Yin, H. Monshizadegan, M. Chang, C. D'Arienzo, S. Scheer, et al.
The Guinea Pig as a Preclinical Model for Demonstrating the Efficacy and Safety of Statins
J. Pharmacol. Exp. Ther.,
February 1, 2008;
324(2):
576 - 586.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Boodhwani and F. W. Sellke
Reply to the Editor.
J. Thorac. Cardiovasc. Surg.,
June 1, 2007;
133(6):
1686 - 1687.
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. R. Westwood, A. Bigley, K. Randall, A. M. Marsden, and R. C. Scott
Statin-Induced Muscle Necrosis in the Rat: Distribution, Development, and Fibre Selectivity
Toxicol Pathol,
February 1, 2005;
33(2):
246 - 257.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. S. MacDonald and M. M. Halleck
The Toxicology of HMG--CoA Reductase Inhibitors: Prediction of Human Risk
Toxicol Pathol,
February 1, 2004;
32(2_suppl):
26 - 41.
[Abstract]
[PDF]
|
|
|
|
|
|
|
I. T. Pyrah, A. Kalinowski, D. Jackson, W. Davies, S. Davis, A. Aldridge, and P. Greaves
Toxicologic Lesions Associated with Two Related Inhibitors of Oxidosqualene Cyclase in the Dog and Mouse
Toxicol Pathol,
February 1, 2001;
29(2):
174 - 179.
[Abstract]
[PDF]
|
|
|
|
|
|
|
M. F Muldoon, S. B Manuck, A. B Mendelsohn, J. R Kaplan, and S. H Belle
Cholesterol reduction and non-illness mortality: meta-analysis of randomised clinical trials
BMJ,
January 6, 2001;
322(7277):
11 - 15.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. M. Walsh and C. E. Rothwell
Hepatic Effects in Beagle Dogs Administered Atorvastatin, a 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitor, for 2 Years
Toxicol Pathol,
July 1, 1999;
27(4):
395 - 401.
[Abstract]
[PDF]
|
|
|
|
|
|
|
R. G. Elkin, Z. Yan, Y. Zhong, S. S. Donkin, K. K. Buhman, J. A. Story, J. J. Turek, R. E. Porter Jr., M. Anderson, R. Homan, et al.
Select 3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase Inhibitors Vary in Their Ability to Reduce Egg Yolk Cholesterol Levels in Laying Hens through Alteration of Hepatic Cholesterol Biosynthesis and Plasma VLDL Composition
J. Nutr.,
May 1, 1999;
129(5):
1010 - 1019.
[Abstract]
[Full Text]
|
|
|
|
|
