Title

HMG-CoA reductase inhibitors: Atorvastatin and simvastatin. Hypocholesterolemic mechanisms of action in the guinea pig

Date of Completion

January 1998

Keywords

Health Sciences, Pharmacology

Degree

Ph.D.

Abstract

Coronary heart disease (CHD) is the number one cause of mortality and morbidity in the United States. Elevated levels of plasma cholesterol are considered a risk factor for CHD. Thus, reducing plasma cholesterol is associated with decreases in CHD risk. HMG-CoA reductase inhibitors or statins are pharmacological agents that lower total plasma cholesterol.^ The purpose of these studies was to determine the specific mechanisms by which atorvastatin (AT) and simvastatin (Sim), two HMG-CoA reductase inhibitors, lower plasma cholesterol. Guinea pigs were used as the animal model because their lipoprotein profile and responses to drugs are similar to humans.^ Guinea pigs were fed hypercholesterolemic diets with different concentrations of AT or Sim. AT and Sim treatment resulted in a dose dependent reduction of plasma LDL cholesterol and apo B concentrations. AT treatment yielded cholesteryl ester depleted LDL, while simvastatin resulted in LDL with higher triacylglycerols. In addition, both drugs were equally effective in decreasing in vitro LDL susceptibility to oxidation and cholesteryl ester transfer protein activity suggesting an important effect of statins in the intravascular processing of lipoproteins.^ Compared to control animals, AT and Sim treated groups had higher number of hepatic apo B/E receptors and faster LDL fractional catabolic rate. In addition, AT treatment resulted in the secretion of less number of VLDL particles suggesting that AT not only accelerated LDL clearance, but also affected VLDL synthesis.^ Simvastatin treatment had no effect on hepatic HMG-CoA reductase mRNA abundance. However, after guinea pigs were fasted for 6-18 h, Sim caused an up-regulation of enzyme activity that might be related to activation of existing protein or protein stabilization once Sim was removed from the active site of the enzyme. In contrast, AT treatment resulted in an increase in HMG-CoA reductase mRNA and no effect on enzyme activity even after 18h of fasting, which suggests that AT continued bound to the enzyme.^ From these studies we conclude that although AT and Sim are equally efficacious in reducing plasma cholesterol, there are important differences between statins in the molecular and metabolic regulation of hepatic enzymes and lipoprotein metabolism. ^