Differentiation of 3-Hydroxy-3-methylglutaryl-coenzyme A Reductase Inhibitors by Their Relative Lipophilicity

Abstract

Certain pharmacological and clinical effects of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, commonly known as statins, can be differentiated on the basis of their lipophilicity. Unlike lipophilic statins, a hydrophilic statin has been reported to be selective for the liver due to lower uptake and lower inhibition of cholesterol synthesis in non-hepatic cells. We compared the lipophilicity of three newer statins, fluvastatin, atorvastatin and cerivastatin, with those of pravastatin, lovastatin and simvastatin, by determining their apparent octanol-water partition coefficients at pH 2, 5, 7 and 7-4. Under physiological pH conditions of 7-7.4, the relative lipophilicity of various statins currently in clinical use was: simvastatin ≅ cerivastatin > lovastatin ≅ fluvastatin ≅ atorvastatin >> pravastatin, where pravastatin is 70- to 300-times more hydrophilic than the other statins.