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CONCLUSIONS

Pharmacodynamics

Atorvastatin inhibits the action of HMG-CoA reductase and thereby decreases endogenous cholesterol synthesis, leading to a decrease in circulating low-density lipoprotein cholesterol. In addition, atorvastatin also reduces triglycerides by limiting VLDL secretion from the liver and increase in clearance of triglyceride-rich lipoprotein.

Other effects of atorvastatin revealed in animal studies are: 

In normal, chow-fed guinea pigs atorvastatin was a more potent cholesterol-lowering drug and unlike lovastatin, lowered plasma triglycerides and VLDL-cholesterol. In casein-fed rabbits with endogenous hypercholesterolemia and in chow-fed rabbits atorvastatin lowered LDL-cholesterol more potently than lovastatin.

Studies in rats showed that atorvastatin and simvastatin  to be nearly equipotent at inhibiting hepatic cholesterol synthesis.

Pharmacokinetics

In mice oral dose produced peak plasma concentrations 1 hr postdose after both single- and multiple-dose administration of [14C]atorvastatin and declined rapidly thereafter. Plasma metabolic profiles, which provided evidence of extensive metabolism, remained similar. Feces was the major route of elimination. Fecal profiles showed extensive metabolism with qualitatively similar profiles after single- and multiple-dose administration. Metabolites identified in plasma and feces include hydroxylated, beta-oxidized, and unsaturated derivatives of atorvastatin. Most metabolites had undergone beta-oxidation.

Bile was a major route of elimination, accounting for 73 and 33% of the oral dose in the rat and dog, respectively. The remaining radioactivity was recovered in the feces; only trace amounts were excreted in urine. Rat and dog plasma profiles after multiple dose administration were similar and showed no additional metabolites not found in bile. Examination of rat and dog bile and plasma indicates that atorvastatin  primarily undergoes oxidative metabolism.

Toxicity

Repeated dose toxicity of atorvastatin 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 atorvastatin, and skeletal muscle changes similar to those described in rats and rabbits were identified.

Studies demonstrate no adverse effects of atorvastatin on fertility and reproduction in rats at doses up to 175 and 225 mg/kg in males and females, respectively.

Atorvastatin, as with the other tested HMG-CoA reductase inhibitors, is not genotoxic. Administration of atorvastatin at 100, 200, or 400 mg/kg per day in mice (producing plasma values of 6 times the mean human drug exposure after an 80 mg dose) for 2 years resulted in a significant increase in liver adenomas in males and liver carcinomas in females.