Subchronic Toxicity of Atorvastatin, a Hydroxymethylglutaryl-Coenzyme A Reductase Inhibitor, in Beagle Dogs

Abstract

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.

The Guinea Pig as a Preclinical Model for Demonstrating the Efficacy and Safety of Statins

“…Although the exact cause of the adverse effects observed at the higher doses of atorvastatin (Ն150 mg/kg) is unknown, all of the animals that died or were sacrificed early before day 10 experienced reduced body weight gain and body weight loss and displayed clinical signs such as reduced grooming and hunched posture. Similar toxicological findings at these doses of atorvastatin have been described for rat (Henck et al, 1998) and dog (Walsh et al, 1996) and are likely due, in part, to adverse effects on liver. Simvastatin was also demonstrated to cause dose-dependent hepatotoxicity in guinea pig (Horsmans et al, 1990).…”

Hepatic Effects in Beagle Dogs Administered Atorvastatin, a 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitor, for 2 Years

“…Unlike L-645,164, another HMGRI, which induced epithelial hyperplasia in gallbladder (7) and AT at s:280 mg/kg (31), AT at 120 mg/kg induced only cholecystitis in this study, although hepatic bile duct proliferation was seen at ?40 mg/kg. Increases in AP consistent with bile duct alterations were sporadic, seen only at 120 mg/kg, and were previously seen at doses of > 150 mg/kg of AT (31).…”

“…Increases in AP consistent with bile duct alterations were sporadic, seen only at 120 mg/kg, and were previously seen at doses of > 150 mg/kg of AT (31). These changes could be due to relatively increased concentrations of AT in bile and gallbladder, since AT is excreted primarily via bile.…”

Lipid-Lowering Medication Use and Aggression Scores in Women: A Report from the NHLBI-Sponsored WISE Study

“…Also, there is accumulating evidence that cholesterol-lowering drugs may adversely affect the brain, cognitive performance, and mood. [12][13][14][15][16] Although such findings are not universal, 17 questions persist about the possible effects of serum cholesterol reduction on suicide and violence, 18,19 and information concerning this issue in women is particularly scarce.…”