New insights into the pharmacodynamic and pharmacokinetic properties of statins

The beneficial effects of statins are assumed to result from their ability to reduce cholesterol biosynthesis, However, because mevalonic acid is the precursor not only of cholesterol, but also of many nonsteroidal isoprenoid compounds, inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase m ay result in pleiotropic effects, It has been shown that several statins de crease smooth muscle cell migration and proliferation and that sera from fl uvastatin-treated patients interfere with its proliferation. Cholesterol ac cumulation in macrophages fan be inhibited by different statins, while both fluvastatin and simvastatin inhibit secretion of metalloproteinases by hum an monocyte-derived macrophages. The antiatherosclerotic effects of statins may be achieved by modifying hypercholesterolemia and the arterial wall en vironment as well. Although statins rarely have severe adverse effects, int eractions with other drugs deserve attention, Simvastatin, lovastatin, ceri vastatin, and atorvastatin are biotransformed in the liver primarily by cyt ochrome P450-3A4, and are susceptible to drug interactions when co-administ ered with potential inhibitors of this enzyme. Indeed, pharmacokinetic inte ractions (e.g., increased bioavailability), myositis, and rhabdomyolysis ha ve been reported following concurrent use of simvastatin or lovastatin and cy closporine A, mibefradil, or nefazodone. In contrast, fluvastatin (mainl y metabolized by cytochrome P450-2C9) and pravastatin (eliminated by other metabolic routes) are less subject to this interaction. Nevertheless, a 5- to 23-fold increase in pravastatin bioavailability has been reported in the presence of cyclosporine A. In summary, statins may have direct effects on the arterial wall, which may contribute to their antiatherosclerotic actio ns, Furthermore, some statins may have lower adverse drug interaction poten tial than others, which is an important determinant of safety during long-t erm therapy. (C) 1999 Elsevier Science Inc, All rights reserved.