Synthetic Lipid-Lowering Agent...

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CRESTOR Rosuvastatin Calcium Is A Synthetic Lipid-Lowering Agent

Rosuvastatin is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, an early and rate-limiting step in cholesterol biosynthesis. Rosuvastatin calcium is bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-
[methyl(methylsulfonyl)amino] pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid] calcium salt. The empirical formula for rosuvastatin calcium is (C22H27FN3O6S)2Ca. Its molecular weight is 1001.14. Its structural formula is: Rosuvastatin calcium is a white amorphous powder that is sparingly soluble in water and methanol, and slightly soluble in ethanol. Rosuvastatin is a hydrophilic compound with a partition coefficient (octanol/water) of 0.13 at pH of 7.0.

CRESTOR Tablets for oral administration contain 5, 10, 20, or 40 mg of rosuvastatin and the following inactive ingredients: microcrystalline cellulose NF, lactose monohydrate NF, tribasic calcium phosphate NF, crospovidone NF, magnesium stearate NF, hypromellose NF, triacetin NF, titanium dioxide USP, yellow ferric oxide, and red ferric oxide NF.
CLINICAL PHARMACOLOGY General: In the bloodstream, cholesterol and triglycerides (TG) circulate as part of lipoprotein complexes. With ultracentrifugation, these complexes separate into very-low-density lipoprotein
(VLDL), intermediate-density lipoprotein (IDL), and low-density lipoprotein (LDL) fractions that contain apolipoprotein B-100 (ApoB-100) and high-density lipoprotein (HDL) fractions.

Cholesterol and TG synthesized in the liver are incorporated into VLDL and secreted into the circulation for delivery to peripheral tissues. TG are removed by the action of lipases, and in a series of steps, the modified VLDL is transformed first into IDL and then into cholesterol-rich LDL. IDL and LDL are removed from the circulation mainly by high affinity ApoB/E receptors, which are expressed to the greatest extent on liver cells. HDL is hypothesized to participate in
the reverse transport of cholesterol from tissues back to the liver.

Epidemiologic, experimental, and clinical studies have established that high LDL cholesterol (LDL-C), low HDL cholesterol (HDL-C), and high plasma TG promote human atherosclerosis and are risk factors for developing cardiovascular disease. In contrast, higher levels of HDL-C are associated with decreased cardiovascular risk.

Like LDL, cholesterol-enriched triglyceride-rich lipoproteins, including VLDL, IDL, and remnants, can also promote atherosclerosis. Elevated plasma triglycerides are frequently found with low HDL-C levels and small LDL particles, as well as in association with non-lipid metabolic risk factors for coronary heart disease (CHD). As such, total plasma TG has not
consistently been shown to be an independent risk factor for CHD. Furthermore, the independent effect of raising HDL or lowering TG on the risk of coronary and cardiovascular morbidity and mortality has not been determined.
Mechanism of Action: Rosuvastatin is a selective and competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts -3-hydroxy-3- methylglutaryl coenzyme A to mevalonate, a precursor of cholesterol. In vivo studies in animals, and in vitro studies in cultured animal and human cells have shown rosuvastatin to have a high uptake into, and selectivity for,
action in the liver, the target organ for cholesterol lowering. In in vivo and in vitro studies, rosuvastatin produces its lipid-modifying effects in two ways. First, it increases the number of hepatic LDL receptors on the cell-surface to enhance uptake and catabolism of LDL. Second, rosuvastatin inhibits hepatic synthesis of VLDL, which reduces the total number of VLDL and LDL particles.

Rosuvastatin reduces total cholesterol (total-C), LDL-C, ApoB, and nonHDL-C (total cholesterol minus HDL-C) in patients with homozygous and heterozygous familial hypercholesterolemia (FH), nonfamilial forms of hypercholesterolemia, and mixed dyslipidemia. Rosuvastatin also reduces TG and produces increases in HDL-C. Rosuvastatin reduces total-C, LDL-C,
VLDL-cholesterol (VLDL-C), ApoB, nonHDL-C and TG, and increases HDL-C in patients with isolated hypertriglyceridemia. The effect of rosuvastatin on cardiovascular morbidity and mortality has not been determined.
Pharmacokinetics and Drug Metabolism Absorption: In clinical pharmacology studies in man, peak plasma concentrations of
rosuvastatin were reached 3 to 5 hours following oral dosing. Both peak concentration (Cmax) and area under the plasma concentration-time curve (AUC) increased in approximate proportion to rosuvastatin dose. The absolute bioavailability of rosuvastatin is approximately 20%.

Administration of rosuvastatin with food decreased the rate of drug absorption by 20% as assessed by Cmax, but there was no effect on the extent of absorption as assessed by AUC. Plasma concentrations of rosuvastatin do not differ following evening or morning drug administration. Significant LDL-C reductions are seen when rosuvastatin is given with or without food, and regardless of the time of day of drug administration. Distribution: Mean volume of distribution at steady-state of rosuvastatin is approximately 134 liters. Rosuvastatin is 88% bound to plasma proteins, mostly albumin. This binding is reversible and independent of plasma concentrations.

Metabolism: Rosuvastatin is not extensively metabolized; approximately 10% of a radiolabeled dose is recovered as metabolite. The major metabolite is N-desmethyl rosuvastatin, which is formed principally by cytochrome P450 2C9, and in vitro studies have demonstrated that N-desmethyl rosuvastatin has approximately one-sixth to one-half the HMG-CoA reductase inhibitory activity of rosuvastatin. Overall, greater than 90% of active plasma HMG-CoA reductase inhibitory activity is accounted for by rosuvastatin. Excretion: Following oral administration, rosuvastatin and its metabolites are primarily excreted in the feces (90%). The elimination half-life (t1/2) of rosuvastatin is approximately 19 hours.
After an intravenous dose, approximately 28% of total body clearance was via the renal route, and 72% by the hepatic route.

If you or anyone you know has taken Crestor and has experienced the above symptoms or side effects, contact our Crestor lawyer and receive a free case evaluation.