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Atorvastatin is not cataractogenic in beagle dogs
D G Robertson1, E R Urda, C E Rothwell
1Department of Pathology and Experimental Toxicology, Parke-Davis Pharmaceutical Research, Division of Warner Lambert Co., Ann Arbor, MI, USA. rober04@aa.wl.com
Insights
Atorvastatin (Lipitor) did not cause cataracts in dogs, even at high doses over two years. This cholesterol-lowering drug appears safer for dog eyes than other reductase inhibitors.
Area of Science:
- Pharmacology
- Ophthalmology
- Veterinary Medicine
Background:
- Atorvastatin is a 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitor used for lipid disorders.
- Other reductase inhibitors have been linked to cataract formation in dogs with prolonged high-dose exposure.
Purpose of the Study:
- To evaluate the potential for atorvastatin to cause cataracts in beagle dogs.
- Assess cataractogenic effects after administration for up to two years.
Main Methods:
- Administered atorvastatin at doses up to 150 mg/kg/day in 2, 13, and 104-week studies.
- Included interim sacrifices and a drug-withdrawal group in the long-term study.
Main Results:
- Significant reduction in serum cholesterol observed across all studies.
- No clinical or histological evidence of drug-induced cataracts was found.
- Minimal, transient changes in lens biochemical parameters at higher doses.
Conclusions:
- Atorvastatin demonstrated no cataractogenic potential in dogs, even with marked cholesterol reduction.
- Atorvastatin appears to be distinct from other reductase inhibitors regarding ocular safety.
Purpose:
Atorvastatin (Lipitor) was developed as an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase for treatment of serum lipid disorders. Other reductase inhibitors (RIs) induce cataracts in dogs exposed to relatively high levels of the drugs for extended periods of time. The purpose of these studies was to assess the cataractogenic potential of atorvastatin, when administered for up to 2 years in beagle dogs.
Methods:
Atorvastatin was administered at doses up to 150 mg/kg/day in 2-week, 13-week or 104-week studies. A 52-week interim sacrifice and a reversal group in which dosing was terminated at week 52 and the dogs sacrificed at week 64, was included in the 104-week study.
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 > or = 40 mg/kg.
Conclusions:
These studies demonstrated that, in spite of marked reduction in serum cholesterol, atorvastatin was not cataractogenic in dogs at any tested dose. We conclude that atorvastatin differs from other RIs in this regard.