Simvastatin
Systematic (IUPAC) name
[(1S,3R,7R,8S,8aR)-8-[2-[(2R,4R)-4-hydroxy-6- oxo-oxan-2-yl]ethyl]-3,7-dimethyl-1,2,3,7,8,8a -hexahydronaphthalen-1-yl]2,2-dimethylbutanoate
Identifiers
CAS number	79902-63-9
ATC code	C10AA01
PubChem	54454
DrugBank	APRD00104
Chemical data
Formula	C25H38O5
Mol. weight	418.566 g/mol
Pharmacokinetic data
Bioavailability	5%
Protein binding	95%
Metabolism	Hepatic (CYP3A4)
Half life	3 hours
Excretion	Renal 13%, faecal 60%
Therapeutic considerations
Pregnancy cat.	D(AU) X(US) Image File history File links Simvastatin. ... IUPAC nomenclature is a systematic way of naming organic chemical compounds. ... CAS registry numbers are unique numerical identifiers for chemical compounds, polymers, biological sequences and alloys. ... The Anatomical Therapeutic Chemical Classification System is used for the classification of drugs. ... A section of the Anatomical Therapeutic Chemical Classification System. ... PubChem is a database of chemical molecules . ... DrugBank is a database available at the University of Alberta that provides information about thousands of products. ... A chemical formula (also called molecular formula) is a concise way of expressing information about the atoms that constitute a particular chemical compound. ... General Name, Symbol, Number carbon, C, 6 Chemical series nonmetals Group, Period, Block 14, 2, p Appearance black (graphite) colorless (diamond) Atomic mass 12. ... General Name, Symbol, Number hydrogen, H, 1 Chemical series nonmetals Group, Period, Block 1, 1, s Appearance colorless Atomic mass 1. ... General Name, Symbol, Number oxygen, O, 8 Chemical series Nonmetals, chalcogens Group, Period, Block 16, 2, p Appearance colorless (gas) very pale blue (liquid) Atomic mass 15. ... The molecular mass of a substance (less accurately called molecular weight and abbreviated as MW) is the mass of one molecule of that substance, relative to the unified atomic mass unit u (equal to 1/12 the mass of one atom of carbon-12). ... In pharmacology, bioavailability is used to describe the fraction of an administered dose of medication that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. ... Many drugs are bound to Blood plasma proteins. ... Metabolism (from Greek μεταβολισμός metabolismos) is the biochemical modification of chemical compounds in living organisms and cells. ... The liver is an organ in vertebrates including humans. ... Cytochrome P450 3A4 (abbreviated CYP3A4) (EC 1. ... The elimination half-life of a drug (or any xenobiotic agent) refers to the timecourse necessary for the quantity of the xenobiotic agent in the body (or plasma concentration) to be reduced to half of its original level through various elimination processes. ... Excretion is the biological process by which an organism chemically separates waste products from its body. ... Kidneys viewed from behind with spine removed The kidneys are bean-shaped excretory organs in vertebrates. ... Feces, faeces, or fæces (see spelling differences) is waste product from an animals digestive tract expelled through the anus (or cloaca) during defecation. ... The pregnancy category of a pharmaceutical agent is an assessment of the risk of fetal injury due to the pharmaceutical, if it is used as directed by the mother during pregnancy. ... Motto: none Anthem(s): Advance Australia Fair Royal anthem: God Save the Queen Capital Canberra Largest city Sydney Official language(s) English (de facto 1) Government Constitutional monarchy (federal)  - Queen Elizabeth II  - Governor-General Michael Jeffery  - Prime Minister John Howard Independence from the UK   - Constitution 1 January 1901   - Statute of... United States is the current Good Article Collaboration of the week! Please help to improve this article to the highest of standards. ...
Legal status	S4(AU) P(UK) ℞-only(US) The regulation of therapeutic goods, that is drugs and therapeutic devices, varies by jurisdiction. ... Motto: none Anthem(s): Advance Australia Fair Royal anthem: God Save the Queen Capital Canberra Largest city Sydney Official language(s) English (de facto 1) Government Constitutional monarchy (federal)  - Queen Elizabeth II  - Governor-General Michael Jeffery  - Prime Minister John Howard Independence from the UK   - Constitution 1 January 1901   - Statute of... United States is the current Good Article Collaboration of the week! Please help to improve this article to the highest of standards. ...
Routes	Oral

Simvastatin (INN) (IPA: [ˈsɪmvəˌstætən]) is a hypolipidemic drug belonging to the class of pharmaceuticals called "statins". It is used to control hypercholesterolemia (elevated cholesterol levels) and to prevent cardiovascular disease. Simvastatin is a synthetic derivate of a fermentation product of Aspergillus terreus. In pharmacology and toxicology, a route of administration is the path by which a drug, fluid, poison or other substance is brought into contact with the body 1. ... An International Nonproprietary Name (INN) is the official non-proprietary or generic name given to a pharmaceutical substance, as designated by the World Health Organization. ... The International Phonetic Alphabet (IPA) is a system of phonetic notation devised by linguists to accurately and uniquely represent each of the wide variety of sounds (phones or phonemes) used in spoken human language. ... Hypolipidemic agents, or antihyperlipidemic agents, are a diverse group of pharmaceuticals that are used in the treatment of hyperlipidemias. ... Lovastatin, the first statin to be marketed The statins (or HMG-CoA reductase inhibitors) form a class of hypolipidemic agents, used as pharmaceuticals to lower cholesterol levels in people at risk for cardiovascular disease because of hypercholesterolemia. ... Hypercholesterolemia (literally: high blood cholesterol) is the presence of high levels of cholesterol in the blood. ... Cholesterol is a sterol (a combination steroid and alcohol) and a lipid found in the cell membranes of all body tissues, and transported in the blood plasma of all animals. ... It has been suggested that this article or section be merged with Coronary heart disease. ...

History

The development of simvastatin was closely linked with the research and development of lovastatin. Biochemist Jesse Huff and his colleagues at Merck began researching the biosynthesis of cholesterol in the early 1950s. In 1956, mevalonic acid was isolated from a yeast extract by Karl Folkers, Carl Hoffman, and others at Merck; while Huff and his associates confirmed that mevalonic acid was an intermediate in cholesterol biosynthesis. In 1959, the HMG-CoA reductase enzyme (a major contributor of internal cholesterol production) was discovered by researchers at the Max Planck Institute. This discovery encouraged scientists worldwide to find an effective inhibitor of this enzyme. Categories: Stub | Hypolipidemic agents ... Merck & Co. ... Mevalonic acid is a key organic compound in biochemistry. ... HMG-CoA reductase HMG-CoA reductase (or 3-hydroxy-3-methyl-glutaryl-CoA reductase or HMGR) is the first enzyme (EC 1. ... The Max-Planck-Gesellschaft zur Förderung der Wissenschaften e. ...

By 1976, Akira Endo had isolated the first inhibitor (compactin ML-236B) from the fungus, Penicillium citrinium in Sankyo, Japan^[1]. In 1979, Hoffman and colleagues isolated lovastatin from a strain of the fungus Aspergillus terreus. While developing and researching lovastatin, Merck scientists synthetically derived a more potent HMG-CoA reductase inhibitor from a fermentation product of Aspergillus terreus, which was designated MK-733 (later to be named simvastatin).^[2] Divisions Chytridiomycota Zygomycota Glomeromycota Ascomycota Basidiomycota Deuteromycota A fungus (plural fungi) is a eukaryotic organism that digests its food externally and absorbs the nutrient molecules into its cells. ... Species Penicillium notatum Penicillium glaucum Penicillium candida Penicillium roqueforti Penicillium marneffei Penicillium bilaiae Penicillium, commonly known as bread mold, is a genus of fungus that includes: Penicillium notatum, which produces the penicillin antibiotic. ... Sankyo means third one in Japanese. ... Species Aspergillus caesiellus Aspergillus candidus Aspergillus carneus Aspergillus clavatus Aspergillus deflectus Aspergillus flavus Aspergillus fumigatus Aspergillus glaucus Aspergillus nidulans Aspergillus niger Aspergillus ochraceus Aspergillus oryzae Aspergillus parasiticus Aspergillus penicilloides Aspergillus restrictus Aspergillus sojae Aspergillus sydowi Aspergillus terreus Aspergillus ustus Aspergillus versicolor Aspergillus is a genus of around 200 fungi (moulds...

Uses

Simvastatin is a powerful lipid-lowering drug that can decrease low density lipoprotein (LDL) levels by up to 50%. It is used in doses of 5 mg up to 80 mg. Higher doses (160 mg) have been found to be too toxic, while giving only minimal benefit in terms of lipid lowering. There is no real effect on HDL and triglyceride levels. Low-density lipoprotein (LDL) refers to a class and range of lipoprotein particles, varying in their size and contents, which carry cholesterol in the blood and around the body, for use by cells. ... The milligram (symbol mg) is an SI unit of mass. ... High density lipoproteins (HDL) form a class of lipoproteins, varying somewhat in their size (8-11 nm in diameter) and contents, that carry cholesterol from the bodys tissues to the liver. ... It has been suggested that Medium Chain Triglycerides be merged into this article or section. ...

From recent research it has become apparent that simvastatin and other statins inhibit the progression of atherosclerosis beyond their effects on LDL. A large number of explanations has been proposed, for example its inhibitory effect on macrophages in the atherosclerotic plaque lesions. A macrophage of a mouse stretching its arms to engulf two particles, possibly pathogens Macrophages (Greek: big eaters, makros = long, phagein = eat) are white blood cells, more specifically phagocytes, acting in the nonspecific defense as well as the specific defense system of vertebrate animals. ... Atherosclerosis is a disease of arterial blood vessels. ...

Rationing

Since its introduction, there has been a large debate surrounding the price for lipid-lowering treatment and its benefits on atherosclerosis. Although this has affected the other statins as well, simvastatin was the first statin drug to be used extensively in clinical practice. Lovastatin, the first statin to be marketed The statins (or HMG-CoA reductase inhibitors) form a class of hypolipidemic agents, used as pharmaceuticals to lower cholesterol levels in people at risk for cardiovascular disease because of hypercholesterolemia. ...

A number of large epidemiological studies were conducted to discover which patients would benefit most from statin drugs; most studies involve simvastatin as the study drug. The most influential studies were the Scandinavian Simvastatin Survival Study (4S) and the Heart protection study (HPS). Epidemiology is the scientific study of factors affecting the health and illness of individuals and populations, and serves as the foundation and logic of interventions made in the interest of public health and preventive medicine. ... The Scandinavian Simvastatin Survival Study (also known under the abbreviation 4S) is a multicenter clinical trial that was performed in 1990s in Scandinavia. ... The Heart Protection Study is a large randomized controlled trial by the Medical Research Council (MRC) in the United Kingdom. ...

It has now become apparent that patients with one or more risk factors for cardiovascular disease (such as diabetes mellitus, hypertension or a positive family history) can benefit from statins—even if they do not have substantially elevated cholesterol levels. It has been suggested that this article or section be merged with Coronary heart disease. ... For the disease characterized by excretion of large amounts of severely diluted urine, see diabetes insipidus. ... For other forms of hypertension see hypertension (disambiguation). ...

Simvastatin was introduced in the late 1980s, and in many countries it is now available as a generic preparation. This has led to a decrease of the price of most statin drugs, and a reappraisal of the health economics of preventive statin treatment. The examples and perspective in this article or section may not represent a worldwide view. ...

In the UK, simvastatin (in a dose of 10mg) has recently become available to purchase from pharmacies without prescription.

Pharmacology

Main article: Statin

All statins act by inhibiting HMG-CoA reductase, the rate-limiting enzyme of the HMG-CoA reductase pathway, the metabolic pathway responsible for the endogenous production of cholesterol. Lovastatin, the first statin to be marketed The statins (or HMG-CoA reductase inhibitors) form a class of hypolipidemic agents, used as pharmaceuticals to lower cholesterol levels in people at risk for cardiovascular disease because of hypercholesterolemia. ... The HMG-CoA reductase pathway, also known as MVA pathway or mevalonate-dependent (MAD) route, is an important cellular metabolic pathway present in virtually all organisms. ... In biochemistry, a metabolic pathway is a series of chemical reactions occurring within a cell, catalyzed by enzymes, resulting in either the formation of a metabolic product to be used or stored by the cell, or the initiation of another metabolic pathway (then called a flux generating step). ... Cholesterol is a sterol (a combination steroid and alcohol) and a lipid found in the cell membranes of all body tissues, and transported in the blood plasma of all animals. ...

The drug is the form of an inactive lactone that is hydrolized after ingestion to produce the active agent. It is a white, nonhygroscopic, crystalline powder that is practically insoluble in water, and freely soluble in chloroform, methanol and ethanol.

Interactions

Grapefruit contains the flavanones naringenin and bergamottin, which inhibit the liver cytochrome P450 3A4. This in turn slows metabolization of simvastatin and a large number of other drugs. Therefore, patients taking simvastatin should restrict their intake of grapefruit and grapefruit-containing products. ^[3] Binomial name Citrus paradisi Macfad. ... Naringenin (not to be confused with naringin)is a flavonone that is considered to have a bioactive effect on human health as antioxidant, free radical scavenger, antiinflammatory, carbohydrate metabolism promoter, immunity system modulater. ... Cytochrome P450 3A4 (abbreviated CYP3A4) (EC 1. ...

Marketing

Zocor Logo

Reference: Drug Discovery Today editorial, 2005.^[4] Image File history File links Zocor. ...

Brand names: Zocor®, Zocor Heart Pro®, marketed by the pharmaceutical company Merck & Co. and Denan (Germany), Liponorm, Sinvacor, Sivastin (Italy), Lipovas (Japan), Lodales (France), Zocord (Austria and Sweden), Zimstat, Simvahexal and Lipex (Australia) and other. A pharmaceutical company, or drug company, is a company licensed to discover, develop, market and distribute drugs. ... Merck & Co. ...

The primary US patent for Zocor expired on June 23, 2006; Ranbaxy Laboratories (at the 80-mg strength) and Teva Pharmaceutical Industries thru its Ivax Pharmaceuticals unit (at all other strengths) were given approval by the FDA to manufacture and sell simvastatin as a generic drug with 180-day exclusivity. Dr. Reddy's Laboratories also has a license from Merck & Co. to sell simvastatin as an authorized generic drug. Ranbaxy Laboratories Limited is an Indian company incorporated in 1961. ... Teva Pharmaceutical Industries Ltd. ... A generic drug (pl. ... Dr. Reddys Laboratories Ltd. ...

Ezetimibe/simvastatin is a combination product to lower lipids and marketed as Vytorin. Vytorin Logo Ezetimibe/simvastatin (IPA: ) is a drug combination used for the treatment of dyslipidemia. ...

Image File history File links Zocor_sales_proportional. ... Image File history File links Zocor_sales_numerical. ...

Sales

Prior to losing U.S. patent protection, simvastatin was Merck & Co.’s largest selling drug and second largest selling cholesterol lowering drug in the world; it recorded 4.3 billion dollars of sales in 2005.^[4] Zocor had an original patent expiration date of January 2006 but was extended by the United States Federal Drug Administration (FDA) o expire on June 23, 2006. The FDA granted the patent extension after Merck & Co, Inc. submitted data from studies of the drug’s positive effect on children, a move typically used by drug companies to lengthen exclusivity.^[4]

Ordinarily, Merck & Co. would have expected a sharp decrease in sales after the generic versions of simvastatin entered the market; however, Merck has slashed the price of Zocor dramatically in an effort to claim sales that would have otherwise gone to the generic versions. At least two major U.S. health insurers, UnitedHealthcare and WellPoint, are now offering Zocor to their members at generic copays.^[5] UnitedHealth Group Incorporated (UnitedHealth Group) is a managed health care company. ... This building in Woodland Hills, California is home to Blue Cross of Californias services for large employers WellPoint, Inc. ...

In addition, since Merck & Co. itself manufactures at least some versions of Dr. Reddy's authorized generic simvastatin, and since only Dr. Reddy's can supply generic simvastatin in all available strengths (unlike Teva and Ranbaxy), Merck & Co. is also poised to profit from the Dr. Reddy's version. An 80mg, 30-count bottle of Dr. Reddy's simvastatin obtained July 6, 2006, states it is made by Merck Sharp & Dohme (Merck & Co.'s name outside the US to avoid conflicts with Merck KGaA) in the UK, just like 80mg Zocor, and has a Merck & Co. logo on the bottom; except for omitting the "80" on one side, the pills are visually identical to 80mg Zocor, including "543" on the other side which is the key part of the National Drug Code for 80mg Zocor. Merck KGaA is a German based pharmaceutical company. ... Each medication listed under Section 510 of the U.S. Federal Food, Drug, and Cosmetic Act is assigned a unique 10-digit, 3-segment number. ...

References

1. ^ Liao and Laufs. Pleiotropic Effects of Statins.(2005) Annu. Rev. Pharmacol.Toxicol:45:89-118
2. ^ Olivia Williams, Anne-Marie Jacks, Jim Davis, Sabrina Martinez (1998). “Case 10: Merck(A): Mevacor*”, Ed. Allan Afuah Innovation Management - Strategies, Implementation, and Profits. Oxford University Press. Retrieved on 2006-07-19.
3. ^ Grapefruit (English). Retrieved on 2006-09-15.
4. ^ ^a b c Maggon, Krishan. "Best-selling human medicines 2002-2004 (editorial)". 2005. Drug Discovery Today, 10(11):739-742
5. ^ Brin, Dinah Wisenberg. "Zocor Patent Expiring Means Bidding War", Associated Press, 2006-06-22. Retrieved on 2006-07-09.

• http://research.businessweek.com/business_summary.asp?Symbol=mrk
• http://money.cnn.com/2002/02/27/companies/merck/#TOP

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See Also

List of drugs affected by grapefruit This page has a list of drugs that are known to be affected by grapefruit. ...

External links

• RxList.com - Simvastatin