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TOXICITY

Single Dose Toxicity

Data on single dose toxicity studies of atorvastatin are not available.

Repeated Dose Toxicity

Results :

2-week toxicity study (daily dosing for 2 week; 3 dose levels)⁽²¹⁾
Doses of 180 mg/kg induced moribundity, necessitating euthanasia.
Weight losses up to 26% were seen at doses ³ 150 mg/kg.
Decreases in cholesterol levels were dose-related.
Alanine and/or aspartate aminotransferase were increased at doses ³ 80 mg/kg; alkaline phosphatase was increased at doses ³150 mg/kg. Histopathologic findings were seen at ³150 mg/kg

12-week rising dose study (daily dosing with weekly increases in dose) ⁽²¹⁾

Hepatocellular degeneration, centrilobular bridging, cholecystitis, hemorrhage in gallbladder and brain, demyelination of optic nerve, and skeletal muscle necrosis at ³ 280 mg/kg.

2-week rising dose study (daily increasing doses for 1 week; maintenance for 1 week) ⁽²¹⁾

Erosion and hemorrhage in large intestine, hepatocellular degeneration and necrosis, and inflammation and necrosis of gallbladder epithelium at 320 mg/kg

13-week toxicity (daily dosing for 13 week; 3 dose levels) ⁽²¹⁾

Doses up to 80 mg/kg for 13 wk did not induce histopathologic lesions in examined organs.

Animal species used	No. of animals	Routes of admn.	Dosage used	Duration
Beagle dogs	Not available	Oral	up to 150 mg/kg/day	2-week, 13-week or 104-week and 52-week interim sacrifice

Results :

Serum cholesterol was significantly lowered in all studies. No clinical or histologic evidence of drug-induced cataracts was found in any study. Lens biochemical analyses in the 13-week study revealed no statistically significant changes in lenticular weight, reduced or oxidized glutathione content, adenosine nucleotide content, glucose-6-phosphate dehydrogenase activity or phosphofructokinase activity in any treatment group. Modest (11-17%) and transient decreases in lens protein, potassium and glucose content were noted in the 13-week study and at week 52 (glucose only) in the 104-week study, at the doses ³ 40 mg/kg.⁽²²⁾