Tissue selectivity of hydroxymethylglutaryl coenzyme A (HMG CoA) reductase inhibitors

Hydroxymethylglutaryl coenzyme A (HMG CoA) reductase inhibitors are a class of lipid-lowering medications, with a major activity on plasma cholesterol levels, now enjoying a vast popularity among physicians and patients. These drugs, affecting a very early and key step of sterol biosynthesis, differ to a large extent in their physicochemical properties, tissue distribution and side effects in animals, possibly in humans. Some of these agents (namely lovastatin and simvastatin) are strikingly lipophilic and require enzymatic conversion from the lactone to the open-ring forms, whereas pravastatin, active per se, is hydrophilic. Liver uptake of pravastatin is regulated by a carrier-mediated mechanism. Other HMG CoA reductase inhibitors have been designed, with the objective of obtaining high levels of hepato-selectivity. Evaluation of available data in terms of potential advantages in tissue, namely liver selectivity, of HMG CoA reductase inhibitors, suggests, that, indeed, altered sterol biosynthesis in a number of tissues may potentially result in the appearance of significant side effects. While there is no clear-cut relationship between tissue selectivity and lipophilicity, the presence of this latter feature seems, in general, to dictate a lesser absorption to peripheral tissues vs the liver. At present, the toxicological profile of major HMG CoA reductase inhibitors appears safe; it is, however, possible that in selected patient groups liver selectivity may offer a considerable therapeutic advantage.