化合物信息

Drug Groups

approved

Description

Fluvastatin is an antilipemic agent that competitively inhibits hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase. HMG-CoA reducuase catalyzes the conversion of HMG-CoA to mevalonic acid, the rate-limiting step in cholesterol biosynthesis. Fluvastatin belongs to a class of medications called statins and is used to reduce plasma cholesterol levels and prevent cardiovascular disease.

Indication

To be used as an adjunct to dietary therapy to prevent cardiovascular events. May be used as secondary prevention in patients with coronary heart disease (CHD) to reduce the risk of requiring coronary revascularization procedures, for reducing progression of coronary atherosclerosis in hypercholesterolemic patients with CHD, and for the treatment of primary hypercholesterolemia and mixed dyslidipidemia.

Pharmacology

Fluvastatin, the first synthetically-derived HMG-CoA reductase inhibitor, is a hydrophilic, acidic, antilipemic agent used to lower cholesterol and triglyceride levels associated with primary hypercholesterolemia and mixed dyslipidemia (Fredrickson types IIa and IIb), to slow the progression of coronary atherosclerosis in patients with CHD and as secondary prevention therapy in patients with CHD to reduce the risk of requiring coronary revascularization procedures. Although similar to lovastatin, simvastatin, and pravastatin, fluvastatin has a shorter half-life, no active metabolites, extensive protein binding, and minimal CSF penetration. Fluvastatin acts primarily in the liver. It is prepared as a racemate of two erythro enantiomers of which the 3R,5S enantiomer exerts the pharmacologic effect.

Toxicity

Generally well-tolerated. May cause GI upset (diarrhea, nausea, constipation, gas, abdominal pain), myotoxicity (mypothy, myositis, rhabdomyolysis), and hepatotoxicity.

Affected Organisms

Biotransformation

Undergoes hepatic metabolism primarily via hydroxylation of the indole ring at the 5- and 6-positions to 5-hydroxy fluvastatin and 6-hydroxy fluvastatin, respectively. N-dealkylation to N-desisopropyl fluvastatin and beta-oxidation of the side chain also occurs. Metabolized primarily by the CYP2C9 isozyme system (75%), and to a lesser extent by CYP3A4 (~20%) and CYP2C8 (~5%). Hydroxylated metabolites retain some pharmcological activity, but are present as conjugates (glucuronides and sulfates) in the blood and are rapidly eliminated via bile into feces.

Absorption

Rapidly and almost completely absorbed (> 90%), but undergoes extensive first pass metabolism. Bioavailability is 24% (range 9-50%).

Half Life

1-3 hours

Protein Binding

98% bound to plasma proteins

Elimination

Fluvastatin is metabolized in the liver, primarily via hydroxylation of the indole ring at the 5- and 6-positions. In vitro studies demonstrated that fluvastatin undergoes oxidative metabolism, predominantly via 2C9 isozyme systems (75%). No significant (<6%) renal excretion of fluvastatin occurs in humans.

Distribution

* 0.35 L/kg

Clearance

* 0.8 L/h/kg
* 107 +/- 38.1 L/h [Hypercholesterolemia patients receiving a single dose of 20 mg]
* 87.8 +/- 45 L/h [Hypercholesterolemia patients receiving 20 mg twice daily]
* 108 +/- 44.7 L/h [Hypercholesterolemia patients receiving 40 mg single]
* 64.2 +/- 21.1 L/h [Hypercholesterolemia patients receiving 40 mg twice daily]

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