Lack of effect of ketoconazole on the pharmacokinetics of rosuvastatin in healthy subjects
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Aims To examine in vivo the effect of ketoconazole on the pharmacokinetics of rosuvastatin, a 3‐hydroxy‐3‐methylglutaryl coenzyme A (HMG‐CoA) reductase inhibitor. Methods This was a randomized, double‐blind, two‐way crossover, placebo‐controlled trial. Healthy male volunteers ( n = 14) received ketoconazole 200 mg or placebo twice daily for 7 days, and rosuvastatin 80 mg was coadministered on day 4 of dosing. Plasma concentrations of rosuvastatin, and active and total HMG‐CoA reductase inhibitors were measured up to 96 h postdose. Results Following coadministration with ketoconazole, rosuvastatin geometric least square mean AUC(0, t ) and C max were unchanged compared with placebo (treatment ratios (90% confidence intervals): 1.016 (0.839, 1.230), 0.954 (0.722, 1.260), respectively). Rosuvastatin accounted for essentially all of the circulating active HMG‐CoA reductase inhibitors and most (> 85%) of the total inhibitors. Ketoconazole did not affect the proportion of circulating active or total inhibitors accounted for by circulating rosuvastatin. Conclusions Ketoconazole did not produce any change in rosuvastatin pharmacokinetics in healthy subjects. The data suggest that neither cytochrome P450 3A4 nor P‐gp‐mediated transport contributes to the elimination of rosuvastatin.Keywords:
Rosuvastatin Calcium
Hydroxymethylglutaryl-CoA reductase
Crossover study
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Rosuvastatin is a new HMG-CoA reductase inhibitor with unique pharmacologic and pharmacokinetic properties. It has additional HMG-CoA reductase enzyme-binding interactions that cause tighter binding, has substantial active transport into hepatocytes, and has the lowest IC50 for sterol synthesis in hepatocytes. Rosuvastatin 10 mg and 80 mg dosages have superior low-density lipoprotein (LDL) cholesterol-lowering efficacy as compared to atorvastatin 10 mg and 80 mg. Rosuvastatin 10 mghas also been shown to have superior LDL reductions to 20 mg of both simvastatin and pravastatin. This agent can raise high-density lipoprotein (HDL) 8% to 12% and lower triglycerides by 10% to 35%. Rosuvastatin is a hydrophilic agent with poor penetration in extrahepatic tissue such as human umbilical vein endothelial cells and fibroblasts. It also has a low potential for cytochrome P450 drug interactions and can be dosed in the morning or night. In conclusion, rosuvastatin is an agent with molecular alterations that provide it with unique pharmacologic and phannacokinetic effects. As such, it is a novel and unique HMG-CoA reductase inhibitor for the treatment of hyperlipidemia.
Rosuvastatin Calcium
Hydroxymethylglutaryl-CoA reductase
Hyperlipidemia
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Rosuvastatin is a hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor used for improving the lipid profile of patients with heterozygous or homozygous familial hypercholesterolaemia, hypertriglyceridaemia or mixed dyslipidaemia. Rosuvastatin has a low propensity for drug interactions and is well tolerated in clinical trials. The pharmacodynamics, pharmacokinetics, drug interactions, pharmacotherapy and safety profiles of rosuvastatin are presented.
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Hydroxymethylglutaryl-CoA reductase
Pharmacotherapy
Rosuvastatin Calcium
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INTRODUCTION Rosuvastatin is an antilipemic agent that competitively inhibits hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase. Rosuvastatin, chemically it is (3R, 5S, 6E)-7-[4-(4-fluorophenyl)-2-(Nmethylmethanesulfonamido)-6-(propan-2-yl) pyrimidin5-yl]-3, 5-dihydroxyhept-6-enoic acid. The chemical formula is C22H28FN3O6S. The molecular weight is 481.538g/mol. Rosuvastatin is a competitive inhibitor of HMG-CoA reductase. HMG-CoA reductase catalyzes the conversion of HMG-CoA to mevalonate, an early ratelimiting step in cholesterol biosynthesis. Decreased hepatic cholesterol concentrations stimulate the upregulation of hepatic low density lipoprotein (LDL) receptors which increases hepatic uptake of LDL. Rosuvastatin also inhibits hepatic synthesis of very low density lipoprotein (VLDL). The overall effect is a decrease in plasma LDL and VLDL [1, 2]. Literature surveys reveal few HPLC and LC-MS methods for its determination [3-10]. The simple, accurate, precise and validated method for determination of Rosuvastatin was developed by LC/MS/MS method.
Coenzyme A
Hydroxymethylglutaryl-CoA reductase
Low-density lipoprotein
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Fenofibrate
Crossover study
Bioequivalence
Open label
Rosuvastatin Calcium
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Dyslipidemia
Rosuvastatin Calcium
Combination therapy
Fenofibrate
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Hydroxymethylglutaryl-CoA reductase
Rosuvastatin Calcium
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Rosuvastatin Calcium
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ABSTRACT Rosuvastatin, a new statin, has been shown to possess a number of advantageous pharmacological properties, including enhanced HMG‐CoA reductase binding characteristics, relative hydrophilicity, and selective uptake into/activity in hepatic cells. Cytochrome P450 (CYP) metabolism of rosuvastatin appears to be minimal and is principally mediated by the 2C9 enzyme, with little involvement of 3A4; this finding is consistent with the absence of clinically significant pharmacokinetic drug‐drug interactions between rosuvastatin and other drugs known to inhibit CYP enzymes. Dose‐ranging studies in hypercholesterolemic patients demonstrated dose‐dependent effects in reducing low‐density lipoprotein cholesterol (LDL‐C) (up to 63%), total cholesterol, and apolipoprotein (apo) B across a 1‐ to 40‐mg dose range and a significant 8.4% additional reduction in LDL‐C, compared with atorvastatin, across the dose ranges of the two agents. Rosuvastatin has also been shown to be highly effective in reducing LDL‐C, increasing high‐density lipo‐protein cholesterol (HDL‐C), and producing favorable modifications of other elements of the atherogenic lipid profile in a wide range of dyslipidemic patients. In patients with mild to moderate hypercholesterolemia, rosuvastatin has been shown to produce large decreases in LDL‐C at starting doses, thus reducing the need for subsequent dose titration, and to allow greater percentages of patients to attain lipid goals, compared with available statins. The substantial LDL‐C reductions and improvements in other lipid measures with rosuvastatin treatment should facilitate achievement of lipid goals and reduce the requirement for combination therapy in patients with severe hypercholesterolemia. In addition, rosuvastatin's effects in reducing triglycerides, triglyceride‐containing lipoproteins, non‐HDL‐C, and LDL‐C and increasing HDL‐C in patients with mixed dyslipidemia or elevated triglycerides should be of considerable value in enabling achievement of LDL‐C and non‐HDL‐C goals in the numerous patients with combined dyslipidemias or metabolic syndrome who require lipid‐lowering therapy. Rosuvastatin is well tolerated alone, and in combination with fenofibrate, extended‐release niacin, and cholestyramine, and has a safety profile similar to that of currently marketed statins. A large, long‐term clinical trials program is under way to investigate the effects of rosuvastatin on atherosclerosis and cardiovascular morbidity and mortality.
Hydroxymethylglutaryl-CoA reductase
Pitavastatin
Rosuvastatin Calcium
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