Individual drugs differ in their ability to mediate the various pleiotropic effects of statins. The lipophilic agents (simvastatin, atorvastatin, cerivastatin, fluvastatin, and lovastatin) have prominent effects on VSMC proliferation and contractility, whereas the more hydrophilic pravastatin has minimal effects. A similar difference has been found for certain actions on leukocytes, such as ROS production and inhibition of LFA-1. On the other hand, effects targeting EC have generally been equivalent, when compared. Most studies have employed one of the lipophilic statins, and thus it is not known whether pravastatin would have similar actions. Because of its hydrophilic nature, pravastatin requires a specific organic anion transporter, LST-1, for its uptake into hepatocytes. The distribution of pravastatin to extrahepatic sites is significantly less than the lipophilic compounds. For those actions dependent upon HMG Co-A reductase inhibition, the potency of the various agents will also depend on their IC50 for this enzyme in a given cell type. In hepatocytes, the IC50 of simvastatin is 8 nM compared with 4.1 and 2.0 nM for lovastatin and pravastatin, respectively. In contrast, the IC50 in myoblasts is 4 nM for simvastatin, compared with 19 and 110 nM for lovastatin and pravastatin, respectively.
The range of serum levels achievable with standard clinical doses of atorvastatin or simvastatin is 0.002 to 0.2 mmol/L. Based on in vitro studies, the main non-cholesterol-lowering effects that would be expected with these concentrations are those targeting endothelial cells. These consist of Akt activation, with resultant phosphoryla-tion and stimulation of eNOS activity and promotion of EC survival. A reduction in EC adhesion molecule expression would also be anticipated, an action that largely appears to be mediated by enhanced eNOS activity. An antiangiogenic effect may occur with concentrations toward the upper end of this range.
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