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| {{drugbox | | __NOTOC__ |
| | IUPAC_name = [8-[2-(4-hydroxy-6-oxo-oxan-2-yl)ethyl] -3,7-dimethyl-1,2,3,7,8,8a- hexahydronaphthalen- 1-yl] 2-methylbutanoate
| | {{Lovastatin}} |
| | image = Lovastatin.png
| | {{CMG}}; {{AE}} {{SS}} |
| | width = 171
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| | CAS_number = 75330-75-5
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| | ATC_prefix = C10
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| | ATC_suffix = AA02
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| | ATC_supplemental =
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| | PubChem = 53232
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| | DrugBank = APRD00370
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| | C=24 | H=36 | O=5
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| | molecular_weight = 404.54 g/mol
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| | bioavailability = <5%
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| | protein_bound = >95%
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| | metabolism = hepatic (CYP3A substrate)
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| | elimination_half-life = 1.1-1.7 hours
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| | excretion = negligible
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| | pregnancy_AU =
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| | pregnancy_US = X
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| | pregnancy_category =
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| | legal_AU =
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| | legal_UK =
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| | legal_US = Rx-only
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| | legal_status =
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| | routes_of_administration = oral
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| }} | |
| {{SI}} | |
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| {{CMG}}
| | '''''For patient information about Lovastatin, click [[Lovastatin (patient information)|here]].''''' |
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| '''Associate Editor-In-Chief:''' {{CZ}}
| | {{SB}} generic, ALTOPREV<sup>®</sup>,ADVICOR® (as a combination with [[niacin]]) |
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| ==[[Lovastatin (patient information)|For patient information, click here]]==
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| ==Overview== | | ==Overview== |
| [[Lovastatin]] is a member of the drug class of [[statin]]s, used for lowering [[cholesterol]] ([[hypolipidemic agent]]) in those with [[hypercholesterolemia]] and so preventing [[cardiovascular disease]].
| | '''Lovastatin''' is a member of the drug class of [[statin]]s, used in combination with diet, weight-loss, and exercise for lowering [[cholesterol]] ([[hypolipidemic agent]]) in those with [[hypercholesterolemia]] to reduce risk of [[cardiovascular disease]]. Lovastatin is a naturally occurring drug found in food such as [[Pleurotus ostreatus|oyster mushrooms]]<ref name="pmid7614366">. |
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| ==History==
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| [[Lovastatin]] was isolated from a strain of ''[[Aspergillus terreus]]'' and it was the first statin approved by the FDA (August 1987).
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| [[Lovastatin]] is also naturally produced by certain higher [[fungus|fungi]] such as ''[[Pleurotus ostreatus]]'' ([[oyster mushroom]]) and closely related ''Pleurotus spp.''<!--
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| --><ref>{{cite journal | author = 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 = 282-6 | year = 1998 | id = PMID 9583372}}</ref>
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| In 1998, the US [[Food and Drug Administration]] (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.
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| 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. <!--
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| --><ref>{{cite journal | author = Vederas, J.C,Moore, R. N., Bigam, G., Chan, K. J.| title = Biosynthesis of the Hypocholesterolemic agent Mevinolin by Aspergillus terreus. Determination of the origin of carbon, Hydrogen and Oxygen by <small>13</small>C NMR and mass Spectrometry | journal = ''''J. Am. Chem. Soc.'''' | volume = '''107''' | pages = 3694-3701 | year = 1985 |}}</ref>
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| However, in 1980, trials with compactin were suspended for undisclosed reasons (rumoured to be related to serious animal toxicity). Because of the close structural similarity between compactin and [[lovastatin]], clinical studies with [[lovastatin]] were also suspended, and additional animal safety studies initiated.
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| 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 resumed.
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| Large-scale trials confirmed the effectiveness of [[lovastatin]]. Observed tolerability continued to be excellent, and [[lovastatin]] was approved by the US FDA in 1987.
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| [[Lovastatin]] at its maximal recommended dose of 80 mg daily produced a mean reduction in [[LDL cholesterol]] of 40%, a far greater reduction than could be obtained with any of the treatments available at the time. Equally important, the drug produced very few adverse effects, was easy for patients to take, and so was rapidly accepted by prescribers and patients. The only important adverse effect is [[myopathy]]/[[rhabdomyolysis]]. This is rare and occurs with all HMG-CoA reductase inhibitors.
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| ==Mechanism of action==
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| [[Lovastatin]] is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase ([[HMG-CoA reductase]]), an enzyme which catalyzes the conversion of HMG-CoA to [[mevalonate]] .<!--
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| --><ref>{{cite journal | author = Alberts, A. W. | title = Discovery, Biochemistry and Biology of Lovastatin | journal = The American Journal of Cardiology | volume = 62 | pages = 10J-15J | year = 1998 |}}</ref>
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| [[Mevalonate]] is a required building block for cholesterol biosynthesis and [[lovastatin]] interferes with its production by acting as a competitive inhibitor for HMG-CoA which binds to the [[HMG-CoA reductase]]. [[Lovastatin]], being inactive in the native form, the form in which it is administered, is hydrolysed to the β-hydroxy acid form in the body and it is this form which is active. Presumably, the reductase acts on the hydrolyzed [[lovastatin]] to reduce the carboxylic acid moiety.
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| ==Discovery, biochemistry and biology==
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| It is now generally accepted that a major risk factor for the development of [[coronary artery disease]] is an elevated concentration of plasma cholesterol, especially [[low density lipoprotein]] (LDL) cholesterol. 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 3 successive condensations of acetyl-CoA units to form a 6-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 isoprenes that are building blocks of squalene, the immediate precursor to sterols, which cyclizes to lanosterol (a methylated sterol) and further metabolized to cholesterol.
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| 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 which catalyzes the conversion of HMG CoA to [[mevalonic acid]] and which has been considered to be a prime target for pharmacologic intervention for several years.<!--
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| --><ref>{{cite journal | author = Alberts, A. W. | title = Discovery, Biochemistry and Biology of Lovastatin | journal = The American Journal of Cardiology | volume = 62 | pages = 10J-15J | year = 1998 |}}</ref>
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| [[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 having a formal sterol ring.
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| [[Lovastatin]] is 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 Endo et al reported discovery of [[mevastatin]], a highly functionalized fungal metabolite, isolated from cultures of Penicillium citrium. [[Mevastatin]] was demonstrated to be an unusually potent inhibitor of the target enzyme and of cholesterol biosynthesis. Subsequent to the first reports describing [[mevastatin]], efforts were initiated to search for other naturally occurring inhibitors oh [[HMG CoA reductase]]. This led to the discovery of a novel fungal metabolite – [[Lovastatin]]. The structure of [[Lovastatin]] was determined to be different from that of [[mevastatin]] by the presence of a 6 alphamethyl group in the hexahydronaphthalene ring.
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| Key points from the study of the Biosynthesis of [[Lovastatin]] :-
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| [[lovastatin|Lovastatin]] is comprised of 2 polyketide chains derived from acetate that are 8- and 4- carbons long coupled in head to tail fashion.
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| 6 alphamethyl group and the methyl group on the 4-carbon side chain are derived from the methyl group of methionine, and
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| 6 alphamethyl group is added before closure of the rings.
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| This implies that [[lovastatin]] is a unique compound synthesized by A. terreus and that [[mevastatin]] is not an intermediate in its formation.
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| ===Cholesterol biosynthetic pathway===
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| [[Image:Cholesterolbiosynthesis.png|thumb|380px|center]]
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| ===[[HMG CoA reductase]] reaction===
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| [[Image:Hmg-reductase.png|thumb|380px|center]]
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| ===Biosynthesis -- Diels-Alder catalyzed cyclization===
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| In vitro formation of a triketide lactone using a genetically-modified protein derived from 6-deoxyerythronolide B synthase has been demonstrated.<!--
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| --><ref>{{cite journal | author = Vederas, J. C., Witter, D. J. | title = Putative Diels-Alder Catalyzed Cyclization during the Biosynthesis of Lovastatin | journal = J. Org. Chem | volume = 61 | issue = 8 | pages = 2613-2623| year = 1996 |}}</ref>
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| The stereochemistry of the molecule supports the intriguing idea that an enzyme-catalyzed Diels-Alder reaction may occur during assembly of the polyketide chain. It thus appears that biological Diels-Alder reactions may be triggered by generation of reactive triene systems on an enzyme surface.
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| [[Image:Biosynthesis-dielsalder.png|thumb|380px|center]]
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| ===Biosynthesis – Using Broadly specific Acyltransferase=== | | ==Category== |
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| It has been found that a dedicated acyltransferase, LovD, is encoded in the [[lovastatin]] biosynthetic pathway. LovD has a broad substrate specificity towards the acyl carrier, the acyl substrate and the decalin acyl acceptor. It efficiently catalyzes the acyl transfer from coenzyme A thoesters or N-acetylcysteamine (SNAC) thioesters to monacolin J.<!--
| | Statins,Carboxylate esters,Lactones,Cardiovascular Drug |
| --><ref>{{cite journal | author = Tang, Y., Wang, C. C., Watanbe, K., Xie, X., Wojcicki, W. A.| title = Biosynthesis of Lovastatin Analogs with Broadly Specific Acyltransferase| journal = Chemistry and Biology| volume = 13 | pages = 1161-1169| year = 2006 |}}</ref>
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| The biosynthesis of [[Lovastatin]] is coordinated by two iterative type I polyketide syntheses and numerous accessory enzymes. Nonketide, the intermediate biosynthetic precursor of [[Lovastatin]], is assembled by the upstream megasynthase LovB (also known as [[lovastatin]] nonaketide synthase), enoylreductase LovC, and CYP450 oxygenases. The five carbon unit side chain is synthesized by LovF (also known as [[lovastatin]] diketide synthase) through a single condensation diketide undergoes methylation and reductive tailoring by the individual LovF catalytic domains to yield an α-S-methylbutyryl thioester covalently attached to the phosphopantetheine arm on the acyl carrier protein (ACP) domain of LovF. Encoded in the gene cluster is a 46kDa protein, LovD, which was initially identified as an esterase homolog. LovD, which was initially identified as an esterase homolog. LovD was suggested to catalyze the last step of lovastatin biosynthesis that regioselectively transacylates the acyl group from LovF to the C8 hydroxyl group of the Nonaketide to yield [[Lovastatin]].
| | ==FDA Package Insert== |
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| [[Image:Biosynthesis-lovd.png|thumb|380px|center]] | | ''' [[Lovastatin indications and usage|Indications and Usage]]''' |
| | | '''| [[Lovastatin dosage and administration|Dosage and Administration]]''' |
| ==Total synthesis==
| | '''| [[Lovastatin dosage forms and strengths|Dosage Forms and Strengths]]''' |
| A major bulk of work in the synthesis of Lovastatin was done by M. Hirama in the 1980’s.<!--
| | '''| [[Lovastatin contraindications|Contraindications]]''' |
| --><ref>{{cite journal | author = Hirama, M., Vet, M. | title = Synthesis of Compactin starting from Naturally occurring building blocks and using an asymmetry inducing reaction | journal = J. Am. Chem. Soc. | volume = 104 | pages = 4251| year = 1982 |}}</ref>
| | '''| [[Lovastatin warnings and precautions|Warnings and Precautions]]''' |
| <!--
| | '''| [[Lovastatin adverse reactions|Adverse Reactions]]''' |
| --><ref>{{cite journal | author = Hirama, M., Iwashita | title = Synthesis of (+)-Mevinolin starting from Naturally occurring building blocks and using an asymmetry inducing reaction | journal = Tetrahedron Lett.| pages = 1811-1812| year = 1983 |}}</ref>
| | '''| [[Lovastatin drug interactions|Drug Interactions]]''' |
| 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 aspartic 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 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 together using 1.3eq sodium hydride in THF followed by reflux in chlorobenzene for 82 hrs under nitrogen to get the enone 3.
| | '''| [[Lovastatin use in specific populations|Use in Specific Populations]]''' |
| | | '''| [[Lovastatin overdosage|Overdosage]]''' |
| Simple organic reactions were used to get to [[Lovastatin]] as shown in the scheme.
| | '''| [[Lovastatin description|Description]]''' |
| | | '''| [[Lovastatin clinical pharmacology|Clinical Pharmacology]]''' |
| ===Synthesis of compounds 1 and 2===
| | '''| [[Lovastatin nonclinical toxicology|Nonclinical Toxicology]]''' |
| | | '''| [[Lovastatin clinical studies|Clinical Studies]]''' |
| [[Image:Totalsynthesis1.png|thumb|280px|center]]
| | '''| [[Lovastatin how supplied storage and handling|How Supplied/Storage and Handling]]''' |
| | | '''| [[Lovastatin patient counseling information|Patient Counseling Information]]''' |
| ===Synthesis of [[lovastatin]]===
| | '''| [[Lovastatin labels and packages|Labels and Packages]]''' |
| | | ==Mechanism of Action== |
| [[Image:Totalsynthesis2.png|thumb|280px|center]] | |
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| ==Pharmacology and dose==
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| {{main|statin}}
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| The mode of action of statins is [[HMG-CoA reductase]] enzyme inhibition. This enzyme is needed by the body to make cholesterol.
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| Lovastatin causes cholesterol to be lost from LDL, but also reduces the concentration of circulating LDL (low density lipoprotein) particles. Apolipoprotein B concentration falls substantially during treatment with [[lovastatin]]. [[Lovastatin]]'s ability to lower LDL is thought to be due to a reduction in VLDL, which is a precursor to LDL. Also, Lovastatin may increase the number of LDL receptors on the surface of cell membranes, and thus increase the breakdown of LDL.
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| [[Lovastatin]] can also produce slight to moderate increases in HDL, and slight to moderate decreases in [[triglycerides]]. Both of these effects are typically beneficial to a patient with a poor lipid profile. | |
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| Both lovastatin and its b-hydroxyacid metabolite are highly bound (>95%) to human plasma proteins. Animal studies demonstrated that lovastatin crosses the blood-brain and placental barriers.<!--
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| --><ref>{{cite web | title=Lovastatin | url=http://www.rxlist.com/cgi/generic/lovastat.htm | publisher=Rxlist.com}}</ref>
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| Elderly patients, or those with [[renal]] insufficiency may have higher plasma concentrations of lovastatin after administration and may require a lower dose. The usual recommended starting dose is 20 mg once a day given with the evening meal, and the dose range is 10-80 mg a day in a single dose, or divided into two doses.
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| ==Side effects==
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| [[Lovastatin]] is usually well tolerated. [[Lovastatin]], and all statin drugs, can rarely cause [[myopathy]] or [[rhabdomyolysis]]. This can be life-threatening if not recognised and treated in time, and so any unexplained muscle pain or weakness whilst on [[lovastatin]] should be promptly mentioned to the prescribing doctor. | |
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| ==Drug interactions==
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| As with all the statin drugs, drinking grapefruit juice during therapy increases the risk of serious side effects. Grapefruit juice inhibits [[CYP3A4]], and thus decreases the metabolism of statins, increasing their plasma concentrations.
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| Lovastatin at doses higher than 20 mg per day should not be used in conjunction with [[gemfibrozil]] or other [[fibrate]]s, [[niacin]], or [[cyclosporin]]. This is because of the significantly increased risk of [[rhabdomyolysis]]. | |
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| ==Pharmacopoeia information==
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| [[Lovastatin]] tablets are preserved in well closed, light resistant containers. Protected from light and stored either in a cool place or at controlled room temperature. | |
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| [[Lovastatin]] tablets are tested for Dissolution and Assay as per the USP. | |
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| Limit for Dissolution – Not less than 80% (Q) of the labeled amount of [[Lovastatin]] is dissolved in 30 mins.
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| Limit for Assay – Each tablet contains not less than 90% and not more than 110% of the labeled amount of Lovastatin, tested by HPLC analysis.
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| [[Lovastatin]] raw material contains 5 impurities – A, B, C, D and E (as shown below). | |
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| ==Brand names==
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| *Mevacor®
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| *Advicor® (as a combination with [[niacin]])
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| *Altocor®
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| *Altoprev®
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| *Statosan® (Atos Pharma)
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| ==See also== | |
| *[[Red yeast rice]]
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| ==References== | | ==References== |
| {{reflist|2}} | | {{Reflist|2}} |
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| {{Statins}} | | {{Statins}} |
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| [[Category:Cardiology]]
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| [[Category:Statins]] | | [[Category:Statins]] |
| [[Category:Drugs]] | | [[Category:Carboxylate esters]] |
| | | [[Category:Lactones]] |
| [[es:Lovastatina]]
| | [[Category:Cardiovascular Drug]] |
| [[nl:Lovastatine]] | | [[Category:Drug]] |
| [[th:โลวาสแตติน]] | |
| [[tr:Lovastatin]] | |
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