New insights into the pharmacodynamic and pharmacokinetic properties of statins

Abstract

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 may result in pleiotropic effects. It has been shown that several statins decrease smooth muscle cell migration and proliferation and that sera from fluvastatin-treated patients interfere with its proliferation. Cholesterol accumulation in macrophages can be inhibited by different statins, while both fluvastatin and simvastatin inhibit secretion of metalloproteinases by human monocyte-derived macrophages. The antiatherosclerotic effects of statins may be achieved by modifying hypercholesterolemia and the arterial wall environment as well. Although statins rarely have severe adverse effects, interactions with other drugs deserve attention. Simvastatin, lovastatin, cerivastatin, and atorvastatin are biotransformed in the liver primarily by cytochrome P450-3A4, and are susceptible to drug interactions when co-administered with potential inhibitors of this enzyme. Indeed, pharmacokinetic interactions (e.g., increased bioavailability), myositis, and rhabdomyolysis have been reported following concurrent use of simvastatin or lovastatin and cyclosporine A, mibefradil, or nefazodone. In contrast, fluvastatin (mainly 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 actions. Furthermore, some statins may have lower adverse drug interaction potential than others, which is an important determinant of safety during long-term therapy.

Introduction

The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) can achieve relatively large reductions in plasma cholesterol levels Brown & Goldstein 1991, Havel & Rapaport 1995 and represent an established class of drugs for the treatment of hypercholesterolemia. Several clinical trials have demonstrated that statins can ameliorate vascular atherosclerosis, and reduce cardiovascular-related morbidity and mortality, in patients with and without coronary artery disease (CAD) symptoms (Brown et al., 1993; Downs et al., 1998; Herd et al., 1997; Jukema et al., 1995; Riegger et al., 1999; Sacks et al., 1996; Scandinavian Simvastatin Survival Study Group, 1994; Shepherd et al., 1995; Long-Term Intervention with Pravastatin in Ischaemic Disease [LIPID] Study Group, 1998). These trials provide a powerful endorsement of the value of lipid-lowering therapy with a statin in patients who are at risk for CAD. Interestingly, there is now a variety of clinical and experimental evidence to show that some statins can interfere with major events involved in the formation of atherosclerotic lesions, independently of their hypolipidemic properties Bellosta et al. 1998a, Corsini et al. 1998, Herd et al. 1997, O'Driscoll et al. 1997, Rosenson & Tangney 1998, Williams et al. 1998. The contribution of these direct vascular effects to the cardiovascular event reduction observed in clinical trials of statins represents one of the major challenges for future studies in order to understand the antiatherosclerotic benefits of these agents.

Together with the identification of new pharmacologic targets, strategies to improve the therapeutic profile of statins will include optimization of safety and tolerability. Although statins rarely have severe adverse effects and are generally well tolerated, interactions with other drugs deserve attention (Garnett, 1995). Indeed, numerous factors contributing to the risk for adverse drug interactions with statins have been reported recently Desager & Horsmans 1996, Jokubaitis 1994, Lennernas & Fager 1997, and should be considered when patients are receiving additional drugs. Knowledge about the differences in the adverse interaction profile of statins is an important determinant of safety in long-term therapy of hypercholesterolemia.

The aim of this review is to discuss the current understanding of the pharmacodynamics and pharmacokinetics of statins. The mechanism(s) of the antiatherosclerotic action of statins that may contribute to the cardiovascular benefits observed in clinical trials and the available information regarding the relevant interactions occurring between statins and other classes of drugs are reviewed.