Hepatic effects in beagle dogs administered atorvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, for 2 years.
The chronic toxicity of atorvastatin (AT), an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, was evaluated in beagle dogs. Dogs were treated with 0, 10, 40, or 120 mg/kg of AT daily. Treatment lengths were 52 wk, 52 wk followed by 12 wk without drug, or 104 wk. Decreases in cholesterol levels were dose related and stable throughout the treatment period. Increases in alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase were transient and dose related in severity at > or = 40 mg/kg. Two dogs administered 120 mg/kg of AT daily were sacrificed moribund during the first 9 wk of treatment. Hepatic lesions were reversible with or without continued treatment and dose related in severity and distribution. Hepatic microgranulomas and hepatocellular degeneration were seen at the 120-mg/kg dose in dogs sacrificed before 53 wk. Before 53 wk, hepatocellular lipofuscin deposits were increased in dogs given > or = 40 mg/kg of AT daily but were similar to controls after 12 wk without drug and after 104 wk of continuous treatment. Bile stasis occurred in dogs given > or = 40 mg/kg of AT daily at all time points but was less severe after reversal and at week 104 compared with week 52.
Walsh
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KM
Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, Michigan 48105, USA.
Rothwell
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CE
D000410:Alanine Transaminase / Q000187:drug effects / Q000378:metabolism; D000469:Alkaline Phosphatase / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001219:Aspartate Aminotransferases / Q000187:drug effects / Q000378:metabolism; D000069059:Atorvastatin; D002784:Cholesterol / Q000378:metabolism; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D006538:Heptanoic Acids / Q000633:toxicity*; D006651:Histocytochemistry; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000633:toxicity*; D008075:Lipoproteins, HDL / Q000187:drug effects / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008854:Microscopy, Electron; D011758:Pyrroles / Q000633:toxicity*; D013997:Time Factors
D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D011758:Pyrroles; D002784:Cholesterol; D000069059:Atorvastatin; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D000469:Alkaline Phosphatase