Lovastatin: Difference between revisions

{{Short description|Chemical compound}}

{{Use dmy dates|date=October 2021}}

{{Infobox drug

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<!-- Clinical data -->

| pronounce =

| tradename = Mevacor, Altocor, others

| DailyMedID = Lovastatin

| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->

| pregnancy_AU_comment =

| pregnancy_category=

| routes_of_administration = [[By mouth]]

| class =

| ATC_prefix = C10

| ATC_suffix = AA02

| ATC_supplemental =

<!-- Legal status -->

| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled -->

| legal_AU_comment =

| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F -->

| legal_BR_comment =

| legal_CA = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII -->

| legal_CA_comment =

| legal_DE = <!-- Anlage I, II, III or Unscheduled -->

| legal_DE_comment =

| legal_NZ = <!-- Class A, B, C -->

| legal_NZ_comment =

| legal_UK = <!-- GSL, P, POM, CD, CD Lic, CD POM, CD No Reg POM, CD (Benz) POM, CD (Anab) POM or CD Inv POM / Class A, B, C -->

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| legal_US = Rx-only

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| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV -->

| legal_UN_comment =

| legal_status = <!-- For countries not listed above -->

<!-- Pharmacokinetic data -->

| bioavailability = <5%<ref name = PK>{{cite journal | vauthors = Neuvonen PJ, Backman JT, Niemi M | title = Pharmacokinetic comparison of the potential over-the-counter statins simvastatin, lovastatin, fluvastatin and pravastatin | journal = Clinical Pharmacokinetics | volume = 47 | issue = 7 | pages = 463–474 | year = 2008 | pmid = 18563955 | doi = 10.2165/00003088-200847070-00003 | s2cid = 11716425 }}</ref>

| protein_bound = >98%<ref name = PK/>

| metabolism = Liver (CYP3A and [[CYP2C8]] substrate)<ref name = PK/>

| metabolites =

| onset =

| elimination_half-life = 2–5 hours<ref name = PK/>

| duration_of_action =

| excretion = Faeces (83%), urine (10%)<ref name = PK/>

<!-- Identifiers -->

| CAS_supplemental =

| IUPHAR_ligand = 2739

| ChEBI_Ref = {{ebicite|correct|EBI}}

| NIAID_ChemDB =

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| synonyms = Monacolin K, Mevinolin

<!-- Chemical and physical data -->

| IUPAC_name = (1''S'',3''R'',7''S'',8''S'',8a''R'')-8-{2-[(2''R'',4''R'')-4-Hydroxy-6-oxooxan-2-yl]ethyl}-3,7-dimethyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl (2''S'')-2-methylbutanoate

| C=24 | H=36 | O=5

| SMILES = O=C(O[C@@H]1[C@H]3C(=C/[C@H](C)C1)\C=C/[C@@H]([C@@H]3CC[C@H]2OC(=O)C[C@H](O)C2)C)[C@@H](C)CC

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<!-- Definition and medical uses -->

'''Lovastatin''', sold under the brand name '''Mevacor''' among others, is a [[statin medication]], to treat [[hypercholesterolemia|high blood cholesterol]] and reduce the risk of [[cardiovascular disease]].<ref name=AHFS2019/> Its use is recommended together with lifestyle changes.<ref name=AHFS2019/> It is taken by mouth.<ref name=AHFS2019/>

<!-- Side effects and mechanisms -->

Common side effects include diarrhea, constipation, headache, muscles pains, rash, and trouble sleeping.<ref name=AHFS2019/> Serious side effects may include [[liver problems]], [[rhabdomyolysis|muscle breakdown]], and [[kidney failure]].<ref name=AHFS2019/> Use during [[pregnancy]] may harm the baby and use during [[breastfeeding]] is not recommended.<ref name=Preg2019>{{cite web |title=Lovastatin Pregnancy and Breastfeeding Warnings |url=https://www.drugs.com/pregnancy/lovastatin.html |website=Drugs.com |access-date=3 March 2019 }}</ref> It works by decreasing the liver's ability to produce cholesterol by blocking the enzyme [[HMG-CoA reductase]].<ref name=AHFS2019>{{cite web |title=Lovastatin Monograph for Professionals |url=https://www.drugs.com/monograph/lovastatin.html |website=Drugs.com |publisher=American Society of Health-System Pharmacists |access-date=3 March 2019 }}</ref>

<!-- Society and culture -->

Lovastatin was patented in 1979 and approved for medical use in 1987.<ref name=Fis2006>{{cite book | vauthors = Fischer J, Ganellin CR |title=Analogue-based Drug Discovery |date=2006 |publisher=John Wiley & Sons |isbn=9783527607495 |page=472 |url=https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA472 }}</ref> It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO22nd">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 22nd list (2021) | year = 2021 | hdl = 10665/345533 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MHP/HPS/EML/2021.02 | hdl-access=free }}</ref> It is available as a [[generic medication]].<ref name=AHFS2019/> In 2021, it was the 100th most commonly prescribed medication in the United States, with more than 6{{nbsp}}million prescriptions.<ref>{{cite web | title=The Top 300 of 2021 | url=https://clincalc.com/DrugStats/Top300Drugs.aspx | website=ClinCalc | access-date=14 January 2024 | archive-date=15 January 2024 | archive-url=https://web.archive.org/web/20240115223848/https://clincalc.com/DrugStats/Top300Drugs.aspx | url-status=live }}</ref><ref>{{cite web | title = Lovastatin - Drug Usage Statistics | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/Lovastatin | access-date = 14 January 2024}}</ref>

The primary uses of lovastatin is for the treatment of [[dyslipidemia]] and the prevention of [[cardiovascular disease]].<ref name=AHFS/> It is recommended to be used only after other measures, such as diet, exercise, and weight reduction, have not improved cholesterol levels.<ref name=AHFS>{{cite web|title=Lovastatin|url=https://www.drugs.com/monograph/Lovastatin.html|work=The American Society of Health-System Pharmacists|access-date=3 April 2011}}</ref>

==Side effects==

Lovastatin is usually well tolerated, with the most common side effects being, in approximately descending order of frequency: [[creatine phosphokinase]] elevation, [[flatulence]], abdominal pain, constipation, [[diarrhoea]], [[myalgia|muscle aches or pains]], nausea, [[dyspepsia|indigestion]], weakness, blurred vision, rash, dizziness and muscle cramps.<ref name = MSR>{{cite web|title=Mevacor, Altoprev (lovastatin) dosing, indications, interactions, adverse effects, and more|work=Medscape Reference|publisher=WebMD|access-date=17 March 2014|url=http://reference.medscape.com/drug/mevacor-altoprev-lovastatin-342458#showall}}</ref> As with all statin drugs, it can occasionally cause [[myopathy]], [[hepatotoxicity]] (liver damage), [[dermatomyositis]] or [[rhabdomyolysis]].<ref name = MSR/> This can be life-threatening if not recognised and treated in time, so any unexplained muscle pain or weakness whilst on lovastatin should be promptly mentioned to the prescribing doctor. Other uncommon side effects that should be promptly mentioned to either the prescribing doctor or an emergency medical service include:<ref name=Medline>{{cite web|title=Lovastatin|url=https://www.nlm.nih.gov/medlineplus/druginfo/meds/a688006.html|work=MedlinePlus|publisher=U.S. National Library of Medicine|access-date=1 December 2012|date=15 June 2012}}</ref>

{{columns-list|colwidth=30em|

* muscle pain, tenderness, or weakness

* lack of energy

* weakness

* fever

* dark colored urine

* [[jaundice]]: yellowing of the skin or eyes

* pain in the upper right part of the stomach

* nausea

* unusual bleeding or bruising

* loss of appetite

* flu-like symptoms

* rash

* hives

* itching

* difficulty breathing or swallowing

* swelling of the face, throat, tongue, lips, eyes, hands, feet, ankles, or lower legs

* hoarseness}}

These less serious side effects should still be reported if they persist or increase in severity:<ref name=Medline/>

{{columns-list|colwidth=30em|

* constipation

* memory loss or forgetfulness

* confusion}}

===Contraindications===

[[Contraindication]]s, conditions that warrant withholding treatment with lovastatin, include pregnancy, breast feeding, and liver disease. Lovastatin is contraindicated during pregnancy (Pregnancy Category X); it may cause birth defects such as skeletal deformities or learning disabilities. Owing to its potential to disrupt infant lipid metabolism, lovastatin should not be taken while breastfeeding.<ref name=LactMed>{{cite web |title=Lovastatin |url=http://toxnet.nlm.nih.gov/cgi-bin/sis/search/f?./temp/~CSZXZ5:1 |work=LactMed |publisher=U.S. National Library of Medicine |access-date=1 December 2012}}</ref> Patients with liver disease should not take lovastatin.<ref name="Rxlist">{{cite web | vauthors = Stöppler M |title=Mevacor Side Effects Center |url=http://www.rxlist.com/mevacor-side-effects-drug-center.htm |publisher=RxList |access-date=1 December 2012}}</ref>

== Interactions ==

As with [[atorvastatin]], [[simvastatin]], and other statin drugs metabolized via [[CYP3A4]], drinking [[grapefruit]] juice during lovastatin therapy may increase the risk of side effects. Components of grapefruit juice, the [[flavonoid]] [[naringin]], or the [[furanocoumarin]] [[bergamottin]] inhibit CYP3A4 ''in vitro'',<ref>{{cite journal | vauthors = Bailey DG, Malcolm J, Arnold O, Spence JD | title = Grapefruit juice-drug interactions | journal = British Journal of Clinical Pharmacology | volume = 46 | issue = 2 | pages = 101–110 | date = August 1998 | pmid = 9723817 | pmc = 1873672 | doi = 10.1046/j.1365-2125.1998.00764.x }}</ref> and may account for the ''in vivo'' effect of grapefruit juice concentrate decreasing the metabolic clearance of lovastatin, and increasing its plasma concentrations.<ref>{{cite journal | vauthors = Kantola T, Kivistö KT, Neuvonen PJ | title = Grapefruit juice greatly increases serum concentrations of lovastatin and lovastatin acid | journal = Clinical Pharmacology and Therapeutics | volume = 63 | issue = 4 | pages = 397–402 | date = April 1998 | pmid = 9585793 | doi = 10.1016/S0009-9236(98)90034-0 | s2cid = 31911751 }}</ref>

Lovastatin is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase), an enzyme that catalyzes the conversion of HMG-CoA to mevalonate.<!--

--><ref name="Alberts98">{{cite journal | vauthors = Alberts AW | title = Discovery, biochemistry and biology of lovastatin | journal = The American Journal of Cardiology | volume = 62 | issue = 15 | pages = 10J–15J | date = November 1988 | pmid = 3055919 | doi = 10.1016/0002-9149(88)90002-1 }}</ref>

Mevalonate is a required building block for cholesterol biosynthesis and lovastatin interferes with its production by acting as a reversible competitive inhibitor for HMG-CoA, which binds to the HMG-CoA reductase. Lovastatin is a [[prodrug]], an inactive lactone in its native form, the gamma-lactone closed ring form in which it is administered, is hydrolysed in vivo to the β-hydroxy acid open ring form; which is the active form.

Lovastatin and other statins have been studied for their [[chemopreventive]] and [[chemotherapeutic]] effects. No such effects were seen in the early studies.<ref>{{cite journal | vauthors = Katz MS | title = Therapy insight: Potential of statins for cancer chemoprevention and therapy | journal = Nature Clinical Practice. Oncology | volume = 2 | issue = 2 | pages = 82–89 | date = February 2005 | pmid = 16264880 | doi = 10.1038/ncponc0097 | s2cid = 9766310 }}</ref> More recent investigations revealed some chemopreventive and therapeutic effects, for certain types of cancer, especially in combination of statins with other anticancer drugs.<ref>{{cite journal | vauthors = Chae YK, Yousaf M, Malecek MK, Carneiro B, Chandra S, Kaplan J, Kalyan A, Sassano A, Platanias LC, Giles F | display-authors = 6 | title = Statins as anti-cancer therapy; Can we translate preclinical and epidemiologic data into clinical benefit? | journal = Discovery Medicine | volume = 20 | issue = 112 | pages = 413–427 | date = December 2015 | pmid = 26760985 }}</ref> It is likely that these effect are mediated by the properties of statins to reduce [[proteasome]] activity, leading to an accumulation of [[cyclin-dependent kinase]] inhibitors [[p21]] and [[p27 (gene)|p27]], and to subsequent G₁-phase arrest, as seen in cells of different cancer lines.<ref>{{cite journal | vauthors = Jakóbisiak M, Bruno S, Skierski JS, Darzynkiewicz Z | title = Cell cycle-specific effects of lovastatin | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 88 | issue = 9 | pages = 3628–3632 | date = May 1991 | pmid = 1673788 | pmc = 51505 | doi = 10.1073/pnas.88.9.3628 | doi-access = free | bibcode = 1991PNAS...88.3628J }}</ref><ref>{{cite journal | vauthors = Rao S, Porter DC, Chen X, Herliczek T, Lowe M, Keyomarsi K | title = Lovastatin-mediated G1 arrest is through inhibition of the proteasome, independent of hydroxymethyl glutaryl-CoA reductase | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 96 | issue = 14 | pages = 7797–7802 | date = July 1999 | pmid = 10393901 | pmc = 22141 | doi = 10.1073/pnas.96.14.7797 | doi-access = free | bibcode = 1999PNAS...96.7797R }}</ref>

==History==

[[Image:Pleurotus ostreatus JPG7.jpg|thumb|left|''[[Pleurotus ostreatus]]'', the oyster mushroom, naturally contains up to 2.8% lovastatin on a dry weight basis.<ref name="pmid12622228">{{cite journal | vauthors = Alarcón J, Aguila S, Arancibia-Avila P, Fuentes O, Zamorano-Ponce E, Hernández M | title = Production and purification of statins from Pleurotus ostreatus (Basidiomycetes) strains | journal = Zeitschrift für Naturforschung C | volume = 58 | issue = 1–2 | pages = 62–64 | date = Jan–Feb 2003 | pmid = 12622228 | doi = 10.1515/znc-2003-1-211 | s2cid = 29392568 | doi-access = free }}</ref>]]

[[Compactin]] and lovastatin, natural products with a powerful inhibitory effect on [[HMG-CoA reductase]], were discovered in the 1970s, and taken into clinical development as potential drugs for lowering [[LDL]] cholesterol.<ref>{{cite journal |vauthors=Vederas JC, Moore RN, Bigam G, Chan KJ |title = Biosynthesis of the hypocholesterolemic agent mevinolin by Aspergillus terreus. Determination of the origin of carbon, hydrogen and oxygen by 13C NMR and mass spectrometry |journal=[[J Am Chem Soc]] |volume=107 |pages=3694–701 |year=1985 |doi=10.1021/ja00298a046 |issue=12}}</ref><ref name="pmid6933445">{{cite journal | vauthors = Alberts AW, Chen J, Kuron G, Hunt V, Huff J, Hoffman C, Rothrock J, Lopez M, Joshua H, Harris E, Patchett A, Monaghan R, Currie S, Stapley E, Albers-Schonberg G, Hensens O, Hirshfield J, Hoogsteen K, Liesch J, Springer J | display-authors = 6 | title = Mevinolin: a highly potent competitive inhibitor of hydroxymethylglutaryl-coenzyme A reductase and a cholesterol-lowering agent | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 77 | issue = 7 | pages = 3957–3961 | date = July 1980 | pmid = 6933445 | pmc = 349746 | doi = 10.1073/pnas.77.7.3957 | doi-access = free | bibcode = 1980PNAS...77.3957A }}</ref>

In 1982, some small-scale clinical investigations of lovastatin, a polyketide-derived natural product isolated from ''Aspergillus terreus'', in very high-risk patients were undertaken, in which dramatic reductions in LDL cholesterol were observed, with very few adverse effects. After the additional animal safety studies with lovastatin revealed no toxicity of the type thought to be associated with compactin, clinical studies continued.

Large-scale trials confirmed the effectiveness of lovastatin. Observed tolerability continued to be excellent, and lovastatin was approved by the US [[Food and Drug Administration|FDA]] in 1987.<ref>[http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Appl_No=019643&TABLE1=OB_Rx FDA Orange Book Detail for application N019643 showing approval for 20 mg tablets on Aug 31, 1987 and 40 mg tablets on Dec 14, 1988]</ref> It was the first statin approved by the FDA.<ref>{{cite journal | vauthors = Endo A | title = The origin of the statins. 2004 | journal = Atherosclerosis. Supplements | volume = 5 | issue = 3 | pages = 125–130 | date = October 2004 | pmid = 15531285 | doi = 10.1016/j.atherosclerosissup.2004.08.033 }}</ref>

Lovastatin is also naturally produced by certain higher [[fungus|fungi]], such as ''[[Pleurotus ostreatus]]'' (oyster mushroom) and closely related ''[[Pleurotus]]'' spp.<ref name="pmid9583372">{{cite journal | vauthors = Bobek P, Ozdín L, Galbavý S | title = Dose- and time-dependent hypocholesterolemic effect of oyster mushroom (Pleurotus ostreatus) in rats | journal = Nutrition | volume = 14 | issue = 3 | pages = 282–286 | date = March 1998 | pmid = 9583372 | doi = 10.1016/S0899-9007(97)00471-1 }}</ref> Research into the effect of oyster mushroom and its extracts on the cholesterol levels of laboratory animals has been extensive,<ref name="pmid12823261">{{cite journal | vauthors = Hossain S, Hashimoto M, Choudhury EK, Alam N, Hussain S, Hasan M, Choudhury SK, Mahmud I | display-authors = 6 | title = Dietary mushroom (Pleurotus ostreatus) ameliorates atherogenic lipid in hypercholesterolaemic rats | journal = Clinical and Experimental Pharmacology & Physiology | volume = 30 | issue = 7 | pages = 470–475 | date = July 2003 | pmid = 12823261 | doi = 10.1046/j.1440-1681.2003.03857.x | s2cid = 39632962 }}</ref><ref name="pmid10555301">{{cite journal | vauthors = Bobek P, Galbavý S | title = Hypocholesterolemic and antiatherogenic effect of oyster mushroom (Pleurotus ostreatus) in rabbits | journal = Die Nahrung | volume = 43 | issue = 5 | pages = 339–342 | date = October 1999 | pmid = 10555301 | doi = 10.1002/(SICI)1521-3803(19991001)43:5<339::AID-FOOD339>3.0.CO;2-5 }}</ref><ref name="pmid9583372"/><ref name="pmid9624732">{{cite journal | vauthors = Opletal L, Jahodár L, Chobot V, Zdanský P, Lukes J, Brátová M, Solichová D, Blunden G, Dacke CG, Patel AV | display-authors = 6 | title = Evidence for the anti-hyperlipidaemic activity of the edible fungus Pleurotus ostreatus | journal = British Journal of Biomedical Science | volume = 54 | issue = 4 | pages = 240–243 | date = December 1997 | pmid = 9624732 }}</ref><ref name="pmid9475042">{{cite journal | vauthors = Bajaj M, Vadhera S, Brar AP, Soni GL | title = Role of oyster mushroom (Pleurotus florida) as hypocholesterolemic/antiatherogenic agent | journal = Indian Journal of Experimental Biology | volume = 35 | issue = 10 | pages = 1070–1075 | date = October 1997 | pmid = 9475042 }}</ref><ref name="pmid9221192">{{cite journal | vauthors = Bobek P, Ozdín L, Kuniak L, Hromadová M | title = [Regulation of cholesterol metabolism with dietary addition of oyster mushrooms (Pleurotus ostreatus) in rats with hypercholesterolemia] | language = sk | journal = Casopis Lekaru Ceskych | volume = 136 | issue = 6 | pages = 186–190 | date = March 1997 | pmid = 9221192 }}</ref><ref name="pmid8810086">{{cite journal | vauthors = Bobek P, Ozdín L, Kuniak L | title = Effect of oyster mushroom (Pleurotus Ostreatus) and its ethanolic extract in diet on absorption and turnover of cholesterol in hypercholesterolemic rat | journal = Die Nahrung | volume = 40 | issue = 4 | pages = 222–224 | date = August 1996 | pmid = 8810086 | doi = 10.1002/food.19960400413 }}</ref><ref name="pmid8869262">{{cite journal | vauthors = Bobek P, Ozdín O, Mikus M | title = Dietary oyster mushroom (Pleurotus ostreatus) accelerates plasma cholesterol turnover in hypercholesterolaemic rat | journal = Physiological Research | volume = 44 | issue = 5 | pages = 287–291 | year = 1995 | pmid = 8869262 }}</ref><ref name="pmid7898579">{{cite journal | vauthors = Bobek P, Ozdin L, Kuniak L | title = The effect of oyster mushroom (Pleurotus ostreatus), its ethanolic extract and extraction residues on cholesterol levels in serum, lipoproteins and liver of rat | journal = Die Nahrung | volume = 39 | issue = 1 | pages = 98–99 | year = 1995 | pmid = 7898579 | doi = 10.1002/food.19950390113 }}</ref><ref name="pmid8197787">{{cite journal | vauthors = Bobek P, Ozdin L, Kuniak L | title = Mechanism of hypocholesterolemic effect of oyster mushroom (Pleurotus ostreatus) in rats: reduction of cholesterol absorption and increase of plasma cholesterol removal | journal = Zeitschrift für Ernährungswissenschaft| volume = 33 | issue = 1 | pages = 44–50 | date = March 1994 | pmid = 8197787 | doi = 10.1007/BF01610577 | s2cid = 41820928 }}</ref><ref name="pmid8218150">{{cite journal | vauthors = Chorváthová V, Bobek P, Ginter E, Klvanová J | title = Effect of the oyster fungus on glycaemia and cholesterolaemia in rats with insulin-dependent diabetes | journal = Physiological Research | volume = 42 | issue = 3 | pages = 175–179 | year = 1993 | pmid = 8218150 }}</ref><ref name="pmid1897899">{{cite journal | vauthors = Bobek P, Ginter E, Jurcovicová M, Kuniak L | title = Cholesterol-lowering effect of the mushroom Pleurotus ostreatus in hereditary hypercholesterolemic rats | journal = Annals of Nutrition & Metabolism | volume = 35 | issue = 4 | pages = 191–195 | year = 1991 | pmid = 1897899 | doi = 10.1159/000177644 }}</ref> although the effect has been demonstrated in a very limited number of human subjects.<ref name="pmid17344789">{{cite journal | vauthors = Khatun K, Mahtab H, Khanam PA, Sayeed MA, Khan KA | title = Oyster mushroom reduced blood glucose and cholesterol in diabetic subjects | journal = Mymensingh Medical Journal | volume = 16 | issue = 1 | pages = 94–99 | date = January 2007 | pmid = 17344789 | doi = 10.3329/mmj.v16i1.261 | doi-broken-date = 7 February 2024 }}</ref>

In 1998, the FDA placed a ban on the sale of dietary supplements derived from [[red yeast rice]], which naturally contains lovastatin, arguing that products containing prescription agents require drug approval.<ref>{{cite journal | vauthors = McCarthy M | year = 1998 | title = FDA bans red yeast rice product | journal = The Lancet | volume = 351 | issue = 9116| page = 1637 | doi = 10.1016/s0140-6736(05)77698-4 | s2cid = 54229753 }}</ref> Judge [[Dale A. Kimball]] of the [[United States District Court for the District of Utah]], granted a motion by Cholestin's manufacturer, Pharmanex, that the agency's ban was illegal under the [[Dietary Supplement Health and Education Act of 1994|1994 Dietary Supplement Health and Education Act]] because the product was marketed as a dietary supplement, not a drug.<ref>[https://www.nytimes.com/1999/02/18/us/cholesterol-treatment-upheld.html Cholesterol Treatment Upheld], The New York Times, 18 February 1999</ref>

[[Image:Lovastatin2.png|180px|thumb|right|A ball-and-stick model of lovastatin]]

The objective is to decrease excess levels of cholesterol to an amount consistent with maintenance of normal body function. Cholesterol is biosynthesized in a series of more than 25 separate enzymatic reactions that initially involves three successive condensations of acetyl-CoA units to form the six-carbon compound 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA). This is reduced to mevalonate and then converted in a series of reactions to the [[isoprene]]s that are building-blocks of [[squalene]], the immediate precursor to sterols, which cyclizes to lanosterol (a methylated sterol) and further metabolized to cholesterol. A number of early attempts to block the synthesis of cholesterol resulted in agents that inhibited late in the biosynthetic pathway between lanosterol and cholesterol. A major rate-limiting step in the pathway is at the level of the microsomal enzyme that catalyzes the conversion of HMG CoA to mevalonic acid, and that has been considered to be a prime target for pharmacologic intervention for several years.<ref name="Alberts98"/>

HMG CoA reductase occurs early in the biosynthetic pathway and is among the first committed steps to cholesterol formulation. Inhibition of this enzyme could lead to accumulation of HMG CoA, a water-soluble intermediate that is, then, capable of being readily metabolized to simpler molecules. This inhibition of reductase would lead to accumulation of lipophylic intermediates with a formal sterol ring.

Lovastatin was the first specific inhibitor of HMG CoA reductase to receive approval for the treatment of hypercholesterolemia. The first breakthrough in efforts to find a potent, specific, competitive inhibitor of HMG CoA reductase occurred in 1976, when [[Akira Endo (biochemist)|Endo]] ''et al.'' reported the discovery of [[mevastatin]], a highly functionalized fungal metabolite, isolated from cultures of ''Penicillium citrium''.<ref>{{cite journal | vauthors = Endo A, Kuroda M, Tsujita Y | title = ML-236A, ML-236B, and ML-236C, new inhibitors of cholesterogenesis produced by Penicillium citrinium | journal = The Journal of Antibiotics | volume = 29 | issue = 12 | pages = 1346–1348 | date = December 1976 | pmid = 1010803 | doi = 10.7164/antibiotics.29.1346 | doi-access = free }}</ref>

===Biosynthesis===

[[File:Domain organization of Lovastatin.gif|thumb|Architecture of the lovastatin type I PKS system. Outlined domains are used iteratively. ACP- acyl carrier protein, AD-alcohol dehydrogenase, AT-acyltransferase, DH-dehydratase, KS-ketoacyl synthase, KR-ketoreductase, MT-methyltransferase, ER-enoylreductase, C-condensation, TE-thioesterase. (*)-redundant domain/inactive not used in this step.]]

[[File:Figure 1- Biosynthesis of Lovastatin.gif|thumb|Biosynthesis of lovastatin]]

The biosynthesis of lovastatin occurs via an iterative type I polyketide synthase (PKS) pathway. The six genes that encode enzymes that are essential for the biosynthesis of lovastatin are lovB, lovC, lovA, lovD, lovG, and lovF .<ref name="Campbell 2010 755–763">{{cite journal | vauthors = Campbell CD, Vederas JC | title = Biosynthesis of lovastatin and related metabolites formed by fungal iterative PKS enzymes | journal = Biopolymers | volume = 93 | issue = 9 | pages = 755–763 | date = September 2010 | pmid = 20577995 | doi = 10.1002/bip.21428 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Xu W, Chooi YH, Choi JW, Li S, Vederas JC, Da Silva NA, Tang Y | title = LovG: the thioesterase required for dihydromonacolin L release and lovastatin nonaketide synthase turnover in lovastatin biosynthesis | journal = Angewandte Chemie | volume = 52 | issue = 25 | pages = 6472–6475 | date = June 2013 | pmid = 23653178 | pmc = 3844545 | doi = 10.1002/anie.201302406 }}</ref> The synthesis of dihydromonacolin L requires a total of 9-malonyl Coa .<ref name="Campbell 2010 755–763"/> It proceeds in the PKS pathway until it reaches '''(E)''' a hexaketide, where it undergoes a Diels-Alder cycloaddition to form the fused rings. After cyclization it continues through the PKS pathway until it reaches '''(I)''' a nonaketide, which then undergoes release from LovB through the thioesterase encoded by LovG. Dihydromonacolin L, '''(J),''' then undergoes oxidation and dehydration via a cytochrome P450 oxygenase encoded by LovA to obtain monacolin J, '''(L)'''.

The MT domain from lovB is active in the conversion of ('''B)''' to ('''C)''' when it transfers a methyl group from S-adenosyl-L-methionine (SAM) to the tetraketide '''(C)''' .<ref name="Campbell 2010 755–763"/> Owing to the fact that LovB contains an inactive ER domain, LovC is required at specific steps to obtain fully reduced products. The domain organization of LovB, LovC, LovG and LovF is shown in Figure 2. The inactive ER domain of lovB is shown with an oval and where LovC acts in trans to LovB is shown with a red box.

In a parallel pathway, the diketide side chain of lovastatin is synthesized by another highly reducing type I polyketide synthase enzyme encoded by LovF . Lastly, the side chain, 2-methylbutyrate '''(M)''' is covalently attached to C-8 hydroxy group of monacolin J '''(L)''' by a transesterase encoded by LovD to form lovastatin.

===Total synthesis===

--><ref>{{cite journal |vauthors=Hirama M, Vet M | title = A chiral total synthesis of compactin | journal = J. Am. Chem. Soc. | volume = 104 | pages = 4251–4253| year = 1982| doi = 10.1021/ja00379a037 | issue = 15}}</ref>

--><ref>{{cite journal | vauthors = Hirama M, Iwashita M | title = Synthesis of (+)-Mevinolin starting from Naturally occurring building blocks and using an asymmetry inducing reaction | journal = Tetrahedron Lett.| pages = 1811–1812| year = 1983 | doi = 10.1016/S0040-4039(00)81777-3| volume = 24 | issue = 17}}</ref>

Hirama synthesized compactin and used one of the intermediates to follow a different path to get to lovastatin. The synthetic sequence is shown in the schemes below. The γ-lactone was synthesized using Yamada methodology starting with glutamic acid. Lactone opening was done using lithium methoxide in [[methanol]] and then [[silylation]] to give a separable mixture of the starting lactone and the [[silyl ether]]. The silyl ether on hydrogenolysis followed by Collins oxidation gave the aldehyde. Stereoselective preparation of (E,E)-diene was accomplished by addition of trans-crotyl phenyl sulfone anion, followed by quenching with [[Acetic anhydride|Ac₂O]] and subsequent reductive elimination of sulfone acetate. Condensation of this with lithium anion of dimethyl methylphosphonate gave compound 1. Compound 2 was synthesized as shown in the scheme in the synthetic procedure. Compounds 1 and 2 were then combined using 1.3 eq sodium hydride in THF followed by reflux in [[chlorobenzene]] for 82 hr under nitrogen to get the enone 3.

<gallery>

Image:Cholesterolbiosynthesis.png|Cholesterol biosynthetic pathway

Image:Hmg-reductase.png|HMG CoA reductase reaction

Image:Biosynthesis-dielsalder.png|Biosynthesis using Diels-Alder catalyzed cyclization

Image:Biosynthesis-lovd.png|Biosynthesis using broadly specific acyltransferase

Image:Totalsynthesis1.png|Synthesis of compounds 1 and 2

Image:Totalsynthesis2.png|Complete lovastatin synthesis

</gallery>

==Society and culture==

===Natural sources===

Lovastatin is a naturally occurring compound found in low concentrations in food such as [[Pleurotus ostreatus|oyster mushrooms]],<ref name="pmid7614366">{{cite journal | vauthors = Gunde-Cimerman N, Cimerman A | title = Pleurotus fruiting bodies contain the inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase-lovastatin | journal = Experimental Mycology | volume = 19 | issue = 1 | pages = 1–6 | date = March 1995 | pmid = 7614366 | doi = 10.1006/emyc.1995.1001 }}</ref> [[red yeast rice]],<ref name="pmid17302963">{{cite journal | vauthors = Liu J, Zhang J, Shi Y, Grimsgaard S, Alraek T, Fønnebø V | title = Chinese red yeast rice (Monascus purpureus) for primary hyperlipidemia: a meta-analysis of randomized controlled trials | journal = Chinese Medicine | volume = 1 | issue = 1 | pages = 4 | date = November 2006 | pmid = 17302963 | pmc = 1761143 | doi = 10.1186/1749-8546-1-4 | doi-access = free }}</ref> and [[Pu-erh]].<ref>{{cite journal | vauthors = Zhao ZJ, Pan YZ, Liu QJ, Li XH | title = Exposure assessment of lovastatin in Pu-erh tea | journal = International Journal of Food Microbiology | volume = 164 | issue = 1 | pages = 26–31 | date = June 2013 | pmid = 23587710 | doi = 10.1016/j.ijfoodmicro.2013.03.018 }}</ref>

===Brand names===

Mevacor, Advicor (as a combination with [[Niacin (substance)|niacin]]), Altocor, Altoprev

===Other applications===

In plant physiology, lovastatin has occasionally been used as inhibitor of [[cytokinin]] biosynthesis.<ref>{{cite journal|vauthors=Hartig K, Beck E |title= Assessment of lovastatin application as tool in probing cytokinin-mediated cell cycle regulation|journal= Physiologia Plantarum|year=2005|volume=125|issue=2|pages=260–267 |doi=10.1111/j.1399-3054.2005.00556.x}}</ref>

== References ==

{{reflist}}

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