Pharmacology of 3‐Hydroxy‐3‐Methylglutaryl‐Coenzyme A Reductase Inhibitors (Statins), Including Rosuvastatin and Pitavastatin

Abstract

Coronary heart disease (CHD) is the leading cause of morbidity and mortality in the Western world, with hypercholesterolemia as the major risk factor. The 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors represent the most efficient drugsfor the treatment of hypercholesterolemia. They lower plasma cholesterol due to the inhibition of endogenous cholesterol synthesis in the liverand subsequent increased expression of low-density lipoprotein (LDL) receptors, resulting in an up-regulated catabolic rate for plasma LDL. The beneficial effect of statins on the incidence of CHD was clearly demonstrated in several large-scale clinical trials. Currently, five statins (atorvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin) are available, and two novel compounds (pitavastatin, rosuvastatin) are undergoing clinical investigation. To point out potential mechanisms leading to increased toxicity and to compare the novel statins with the established ones, this article summarizes their pharmacological data since the prevalence of adverse events can be explained at least in part by their pharmacokinetic differences.

Update on Statins: 2003

“…However, atorvastatin, fluvastatin, and rosuvastatin exhibit additional binding via their fluorophenyl groups and the HMG-CoA reductase Arg590 residue, but they differ widely in their relative LDL-C lowering. 3 The statins differ in their absorption, plasma protein binding, excretion, and solubility (Table 1) and exhibit variable dose-related efficacy in reducing LDL-C. 4 In general, LDL-C is reduced by an additional 7% with each doubling of the statin dose. 5 In addition, in patients with hypertriglyceridemia, statins achieve a 22% to 45% reduction in triglyceride levels because of decreased hepatic secretion of VLDL.…”

Therapeutic potential of statins in multiple sclerosis: immune modulation, neuroprotection and neurorepair

“…However, recent clinical and experimental studies have documented a variety of statins' pleiotropic effects, such as anti-inflammatory, antiproliferative, antithrombotic and antioxidant activities in various pathological conditions [7][8][9][10][11][12][13][14][15][16][17].…”

“…The inhibition of HMG-CoA reductase by naturally occurring (lovastatin, mevastatin and simvastatin) and synthetic statins (fluvastatin, atorvastatin and rosuvastatin) inhibits the mevalonate pathway leading to the reduction of mevalonate pathway biologically active metabolites, including isoprenoids, dolichol, ubiquinone and cholesterol ( Figure 1). The efficacy of different statins varies depending upon their bioavailability governed by their hydrophobicity and their turnover by the cytochrome P450 enzyme system [12]. Secondly, the bioavailability of statins is also affected by polymorphisms in genes coding for ApoE, ABC drug transporters, HMG-CoA reductase and the cytochrome P450 enzyme system [18].…”

Bayesian statistic methods and theri application in probabilistic simulation models

“…Sul piano clinico le statine presentano una diversa correlazione dose-effetto per la riduzione delle LDL-C [26]. In generale, raddoppiando la dose di statina si ottiene un ulteriore incremento del 7% circa nella riduzione dei livelli di LDL-C [27].…”