Hydrophilicity/lipophilicity: Relevance for the Pharmacology and Clinical Effects of HMG-CoA Reductase Inhibitors

The recent development of specific competitive inhibitors of the hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase such as lovastatin, simvastatin, pravastatin and fluvastatin has provided an important new and effective approach to the treatment of hyperlipidaemia and atherosclerosis. These agents are designed to be hepatoselective because the primary site of cholesterol synthesis is the liver and peripheral inhibition of cholesterol synthesis would be more likely to cause adverse drug effects. In this review, Bettina Hamelin and Jacques Turgeon discuss how specific physico-chemical and pharmacological properties (first-pass effect or carrier-mediated uptake) confer hepatoselectivity to either lipophilic or hydrophilic HMG-CoA reductase inhibitors.