Pharmacology and mechanism of action of the new HMG-CoA reductase inhibitors

Abstract

The new inhibitors of hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase are synthetic compounds, of fungal origin, inhibiting a key and unidirectional enzyme in the sterol biosynthetic pathway. Lovastatin, simvastatin and pravastatin, currently available, differ, to some extent: lovastatin and simvastatin are inactive pro-drugs, undergoing conversion by the liver, most of their metabolites active. Pravastatin is instead active per se with mostly inactive metabolites. Distribution of the drugs and of their metabolites in different tissues, also depending upon the relative inhibitory activity, may result in different cholesterol lowering potency as well as in, eventually, some tissue selectivity. Otherwise, the plasma kinetics of the three agents is rather short, usually with a progressive decay of activity within 24 h from administration. Enzyme inhibition results in the upregulation of high affinity receptors for low density lipoproteins (LDL), whose clearance is markedly raised after treatment. Otherwise, HMG-CoA reductase inhibitors do not affect to a significant extent the levels and/or composition of the other major lipoprotein fractions.