Review articleNew insights into the pharmacodynamic and pharmacokinetic properties of statins
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.
Section snippets
Direct antiatherosclerotic properties of statins: evidence for new pharmacologic targets
In patients with atherosclerosis, it has been assumed that any beneficial effects of statins are linked to their hypolipidemic properties Feussner 1994, Hunninghake 1992, Kjekshus et al. 1996, thus suggesting that the hypolipidemic effect is the main mechanism for preventing the development of atherosclerosis. However, since mevalonic acid (MVA), the product of the effect of HMG-CoA reductase on HMG-CoA, is the precursor not only of cholesterol, but also of numerous metabolites Goldstein &
Clinical pharmacokinetics of statins with reference to drug interactions
The issue of safety and drug tolerance is particularly important in primary and secondary prevention of cardiovascular disease, where the risks of long-term therapy must be considered in the context of achievable benefits. In general, statin monotherapy is well tolerated and has a low frequency of adverse events Dujovne et al. 1991, Hsu et al. 1995. The most important adverse effects associated with statins are myopathy and asymptomatic increase in hepatic transaminases, which occur rarely
Conclusions
HMG-CoA reductase inhibitors, beyond their lipid-lowering properties, exert a direct antiatherosclerotic effect on the arterial wall that could prevent significant cardiovascular disease. Clinical trials have demonstrated that statins greatly reduce cardiovascular-related morbidity and mortality in patients with and without symptoms of CAD. Several issues remain to be addressed, however, before drawing any conclusion as to the therapeutic benefit of the pleiotropic effects of statins. For
References (182)
- et al.
Cardiovascular complications after renal transplantation
Transplant Proc
(1998) - et al.
Lovastatin inhibits low-density lipoprotein oxidation and alters its fluidity and uptake by macrophagesin vitro and in vivo studies
Metabolism
(1992) - et al.
In vitro and in vivo apoptosis by atorvastatin in stimulated smooth muscle cells
Pharmacol Res
(1997) - et al.
Inhibitory effect of fluvastatin at doses insufficient to lower serum lipids on the catheter-induced thickening of intima in rabbit femoral artery
Eur J Pharmacol
(1996) - et al.
Direct vascular effects of HMG-CoA reductase inhibitors
Atherosclerosis
(1998) - et al.
Requirement for mevalonate in acetylated LDL induction of cholesterol esterification in macrophages
Atherosclerosis
(1993) - et al.
Antiatherosclerotic activity of inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase in cholesterol-fed rabbitsa biochemical and morphological evaluation
Atherosclerosis
(1994) - et al.
The HMG-CoA reductase inhibitors atorvastatin and lovastatin reduce accumulation of collagenase and 92-kD gelatinase released by cultured human monocytic and vascular smooth muscle cells
Atherosclerosis
(1997) - et al.
Metabolism and drug interactions of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors in transplant patientsare the statins mechanistically similar?
Pharmacol Ther
(1998) - et al.
Relationship between mevalonate pathway and arterial myocyte proliferationin vitro studies with inhibitors of HMG-CoA reductase
Atherosclerosis
(1993)
Pharmacology of competitive inhibitors of HMG-CoA reductase
Pharmacol Res
Inhibitor of proliferation of arterial smooth-muscle cells by fluvastatin
Lancet
Post-translational modification of human brain type I inositol-1,4,5-trisphosphate 5-phosphatase by farnesylation
J Biol Chem
Rhabdomyolysis after taking atorvastatin with gemfibrozil
Am J Cardiol
The discovery and development of HMG-CoA reductase inhibitors
J Lipid Res
Simvastatin during warfarin therapy in hyperlipoproteinaemia
Lancet
Effect of lovastatin on intimal hyperplasia after balloon angioplasty. A study in an atherosclerotic hypercholesterolemic rabbit
J Am Coll Cardiol
Simvastatin inhibits the oxidation of low-density lipoproteins by activated human monocyte-derived macrophages
Biochim Biophys Acta
Prenyl proteins in eukaryotic cellsa new type of membrane anchor
Trends Biochem Sci
Branch-point reactions in the biosynthesis of cholesterol, dolichol, ubiquinone and prenylated proteins
Biochim Biophys Acta
Hydrophilicity/lipophilicityrelevance for the pharmacology and clinical effects of HMG-CoA reductase inhibitors
Trends Pharmacol Sci
Effects of fluvastatin on coronary atherosclerosis in patients with mild to moderate cholesterol elevations (Lipoprotein and Coronary Atherosclerosis Study [LCAS])
Am J Cardiol
Effect of fluvastatin for safely lowering atherogenic lipids in renal transplant patients receiving cyclosporine A
Am J Cardiol
Reduced susceptibility of low density lipoprotein (LDL) to lipid peroxidation after fluvastatin therapy in associated with the hypocholesterolemic effect of the drug and its binding to the LDL
Atherosclerosis
Gβγ interaction with PH domains and Ras-MPK signaling pathways
Trends Biochem Sci
Lovastatin induces growth inhibition and apoptosis in human malignant glioma cells
Biochem Biophys Res Commun
Pravastatin sodium activates endothelial nitric oxide synthase independently of its cholesterol-lowering actions
J Am Coll Cardiol
Therapy of hyperlipidemia with lovastatin in kidney transplant patients on cyclosporine A immunosuppressionthree-year experience
Transplant Proc
Biotransformation of pravastatin sodium
Biochem Biophys Res Commun
Lovastatinwarfarin interaction
Arch Intern Med
Inhibition of proliferation of human smooth muscle cells by various HMG-CoA reductase inhibitors; comparison with other human cell types
Biochim Biophys Acta
FDA announce new drug-interaction warnings for mibefradil
Am J Health Syst Pharm
Clinical pharmacokinetics of fluvastatin with reference to other HMG-CoA reductase inhibitors
Drugs Today
Plasma concentration profiles of simvastatin 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitory activity in kidney transplant recipients with and without ciclosporin
Nephron
Low-dose simvastatin is a well tolerated and efficacious cholesterol-lowering agent in ciclosporin-treated kidney transplant recipientsdouble-blind, randomized, placebo-controlled study in 40 patients
Nephron
Lovastatin and rhabdomyolisis
Ann Intern Med
Mevalonate modulation of cell proliferation and apoptosis
Oncol Rep
Drug interactions of lipid-altering drugs
Drug Safety
HMG-CoA reductase inhibitors reduce MMP-9 secretion by macrophages
Arterioscler Thromb Vasc Biol
HMG-CoA reductase inhibitors reduce acetyl LDL endocytosis in mouse peritoneal macrophages
Arterioscler Thromb Vasc Biol
Use of in vitro and in vivo data to estimate the likelihood of metabolic pharmacokinetic interactions
Clin Pharmacokinet
Apoptosis participates in cellularity regulation during rat aortic intimal thickening
Am J Pathol
Coronary artery disease in renal transplant recipients
Cleve Clin J Med
Lipid lowering and plaque regressionnew insights into prevention of plaque disruption and clinical events in coronary disease
Circulation
Drugs used in the treatment of hyperlipoproteinemias
Effect of partial ileal bypass surgery on mortality and morbidity from coronary heart disease in patients with hypercholesterolemia. Report of the Program on the Surgical Control of the Hyperlipidemias (POSCH)
N Engl J Med
Influence of age and gender on the plasma profiles of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitory activity following multiple doses of lovastatin and simvastatin
Pharm Res
Differential effects of lovastatin on the trafficking of endogenous and lipoprotein-derived cholesterol in human monocyte-derived macrophages
Arterioscler Thromb Vasc Biol
Multiple-dose pharmacokinetics, pharmacodynamics, and safety of atorvastatin, an inhibitor of HMG-CoA reductase, in healthy subjects
Clin Pharmacol Ther
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