Lovastatin - Wikipedia

Lovastatin, sold under the brand name Mevacor among others, is a statin medication, to treat high blood cholesterol and reduce the risk of cardiovascular ... Lovastatin FromWikipedia,thefreeencyclopedia Jumptonavigation Jumptosearch Chemicalcompound LovastatinClinicaldataTradenamesMevacor,Altocor,othersOthernamesMonacolinK,MevinolinAHFS/Drugs.comMonographMedlinePlusa688006Licensedata US DailyMed: Lovastatin RoutesofadministrationBymouthATCcodeC10AA02(WHO)LegalstatusLegalstatus US:℞-only PharmacokineticdataBioavailability<5%[1]Proteinbinding>98%[1]MetabolismLiver(CYP3AandCYP2C8substrate)[1]Eliminationhalf-life2–5hours[1]ExcretionFaeces(83%),urine(10%)[1]Identifiers IUPACname (1S,3R,7S,8S,8aR)-8-{2-[(2R,4R)-4-Hydroxy-6-oxooxan-2-yl]ethyl}-3,7-dimethyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl(2S)-2-methylbutanoate CASNumber75330-75-5 YPubChemCID53232IUPHAR/BPS2739DrugBankDB00227 YChemSpider48085 YUNII9LHU78OQFDKEGGD00359 YChEBICHEBI:40303 YChEMBLChEMBL503 YCompToxDashboard(EPA)DTXSID5020784ECHAInfoCard100.115.931ChemicalandphysicaldataFormulaC24H36O5Molarmass404.547 g·mol−13Dmodel(JSmol)Interactiveimage 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 InChI InChI=1S/C24H36O5/c1-5-15(3)24(27)29-21-11-14(2)10-17-7-6-16(4)20(23(17)21)9-8-19-12-18(25)13-22(26)28-19/h6-7,10,14-16,18-21,23,25H,5,8-9,11-13H2,1-4H3/t14-,15-,16-,18+,19+,20-,21-,23-/m0/s1 YKey:PCZOHLXUXFIOCF-BXMDZJJMSA-N Y   (verify) Lovastatin,soldunderthebrandnameMevacoramongothers,isastatinmedication,totreathighbloodcholesterolandreducetheriskofcardiovasculardisease.[2]Itsuseisrecommendedtogetherwithlifestylechanges.[2]Itistakenbymouth.[2] Commonsideeffectsincludediarrhea,constipation,headache,musclespains,rash,andtroublesleeping.[2]Serioussideeffectsmayincludeliverproblems,musclebreakdown,andkidneyfailure.[2]Useduringpregnancymayharmthebabyanduseduringbreastfeedingisnotrecommended.[3]Itworksbydecreasingtheliver'sabilitytoproducecholesterolbyblockingtheenzymeHMG-CoAreductase.[2] Lovastatinwaspatentedin1979andapprovedformedicalusein1987.[4]ItisontheWorldHealthOrganization'sListofEssentialMedicines.[5]Itisavailableasagenericmedication.[2]In2019,itwasthe95thmostcommonlyprescribedmedicationintheUnitedStates,withmorethan8 millionprescriptions.[6][7] Contents 1Medicaluses 2Sideeffects 2.1Contraindications 2.2Interactions 3Mechanismofaction 4History 4.1Biosynthesis 4.2Totalsynthesis 5Societyandculture 5.1Naturalsources 5.2Brandnames 5.3Otherapplications 6Seealso 7References 8Externallinks Medicaluses[edit] Theprimaryusesoflovastatinisforthetreatmentofdyslipidemiaandthepreventionofcardiovasculardisease.[8]Itisrecommendedtobeusedonlyafterothermeasures,suchasdiet,exercise,andweightreduction,havenotimprovedcholesterollevels.[8] Sideeffects[edit] Lovastatinisusuallywelltolerated,withthemostcommonsideeffectsbeing,inapproximatelydescendingorderoffrequency:creatinephosphokinaseelevation,flatulence,abdominalpain,constipation,diarrhoea,muscleachesorpains,nausea,indigestion,weakness,blurredvision,rash,dizzinessandmusclecramps.[9]Aswithallstatindrugs,itcanrarelycausemyopathy,hepatotoxicity(liverdamage),dermatomyositisorrhabdomyolysis.[9]Thiscanbelife-threateningifnotrecognisedandtreatedintime,soanyunexplainedmusclepainorweaknesswhilstonlovastatinshouldbepromptlymentionedtotheprescribingdoctor.Otheruncommonsideeffectsthatshouldbepromptlymentionedtoeithertheprescribingdoctororanemergencymedicalserviceinclude:[10] musclepain,tenderness,orweakness lackofenergy weakness fever darkcoloredurine jaundice:yellowingoftheskinoreyes painintheupperrightpartofthestomach nausea unusualbleedingorbruising lossofappetite flu-likesymptoms rash hives itching difficultybreathingorswallowing swellingoftheface,throat,tongue,lips,eyes,hands,feet,ankles,orlowerlegs hoarseness Theselessserioussideeffectsshouldstillbereportediftheypersistorincreaseinseverity:[10] constipation memorylossorforgetfulness confusion Contraindications[edit] Contraindications,conditionsthatwarrantwithholdingtreatmentwithlovastatin,includepregnancy,breastfeeding,andliverdisease.Lovastatiniscontraindicatedduringpregnancy(PregnancyCategoryX);itmaycausebirthdefectssuchasskeletaldeformitiesorlearningdisabilities.Owingtoitspotentialtodisruptinfantlipidmetabolism,lovastatinshouldnotbetakenwhilebreastfeeding.[11]Patientswithliverdiseaseshouldnottakelovastatin.[12] Interactions[edit] Aswithatorvastatin,simvastatin,andotherstatindrugsmetabolizedviaCYP3A4,drinkinggrapefruitjuiceduringlovastatintherapymayincreasetheriskofsideeffects.Componentsofgrapefruitjuice,theflavonoidnaringin,orthefuranocoumarinbergamottininhibitCYP3A4invitro,[13]andmayaccountfortheinvivoeffectofgrapefruitjuiceconcentratedecreasingthemetabolicclearanceoflovastatin,andincreasingitsplasmaconcentrations.[14] Mechanismofaction[edit] Lovastatinisaninhibitorof3-hydroxy-3-methylglutaryl-coenzymeAreductase(HMG-CoAreductase),anenzymethatcatalyzestheconversionofHMG-CoAtomevalonate.[15] MevalonateisarequiredbuildingblockforcholesterolbiosynthesisandlovastatininterfereswithitsproductionbyactingasareversiblecompetitiveinhibitorforHMG-CoA,whichbindstotheHMG-CoAreductase.Lovastatinisaprodrug,aninactivelactoneinitsnativeform,thegamma-lactoneclosedringforminwhichitisadministered,ishydrolysedinvivototheβ-hydroxyacidopenringform;whichistheactiveform. Lovastatinandotherstatinshavebeenstudiedfortheirchemopreventiveandchemotherapeuticeffects.Nosucheffectswereseenintheearlystudies.[16]Morerecentinvestigationsrevealedsomechemopreventiveandtherapeuticeffects,forcertaintypesofcancer,especiallyincombinationofstatinswithotheranticancerdrugs.[17]Itislikelythattheseeffectaremediatedbythepropertiesofstatinstoreduceproteasomeactivity,leadingtoanaccumulationofcyclin-dependentkinaseinhibitorsp21andp27,andtosubsequentG1-phasearrest,asseenincellsofdifferentcancerlines.[18][19] History[edit] Pleurotusostreatus,theoystermushroom,naturallycontainsupto2.8%lovastatinonadryweightbasis.[20] Compactinandlovastatin,naturalproductswithapowerfulinhibitoryeffectonHMG-CoAreductase,werediscoveredinthe1970s,andtakenintoclinicaldevelopmentaspotentialdrugsforloweringLDLcholesterol.[21][22] In1982,somesmall-scaleclinicalinvestigationsoflovastatin,apolyketide-derivednaturalproductisolatedfromAspergillusterreus,inveryhigh-riskpatientswereundertaken,inwhichdramaticreductionsinLDLcholesterolwereobserved,withveryfewadverseeffects.Aftertheadditionalanimalsafetystudieswithlovastatinrevealednotoxicityofthetypethoughttobeassociatedwithcompactin,clinicalstudiescontinued. Large-scaletrialsconfirmedtheeffectivenessoflovastatin.Observedtolerabilitycontinuedtobeexcellent,andlovastatinwasapprovedbytheUSFDAin1987.[23]ItwasthefirststatinapprovedbytheFDA.[24] Lovastatinisalsonaturallyproducedbycertainhigherfungi,suchasPleurotusostreatus(oystermushroom)andcloselyrelatedPleurotusspp.[25]Researchintotheeffectofoystermushroomanditsextractsonthecholesterollevelsoflaboratoryanimalshasbeenextensive,[26][27][25][28][29][30][31][32][33][34][35][36]althoughtheeffecthasbeendemonstratedinaverylimitednumberofhumansubjects.[37] In1998,theFDAplacedabanonthesaleofdietarysupplementsderivedfromredyeastrice,whichnaturallycontainslovastatin,arguingthatproductscontainingprescriptionagentsrequiredrugapproval.[38]JudgeDaleA.KimballoftheUnitedStatesDistrictCourtfortheDistrictofUtah,grantedamotionbyCholestin'smanufacturer,Pharmanex,thattheagency'sbanwasillegalunderthe1994DietarySupplementHealthandEducationActbecausetheproductwasmarketedasadietarysupplement,notadrug.[39] Aball-and-stickmodeloflovastatin Theobjectiveistodecreaseexcesslevelsofcholesteroltoanamountconsistentwithmaintenanceofnormalbodyfunction.Cholesterolisbiosynthesizedinaseriesofmorethan25separateenzymaticreactionsthatinitiallyinvolvesthreesuccessivecondensationsofacetyl-CoAunitstoformthesix-carboncompound3-hydroxy-3-methylglutarylcoenzymeA(HMGCoA).Thisisreducedtomevalonateandthenconvertedinaseriesofreactionstotheisoprenesthatarebuilding-blocksofsqualene,theimmediateprecursortosterols,whichcyclizestolanosterol(amethylatedsterol)andfurthermetabolizedtocholesterol.Anumberofearlyattemptstoblockthesynthesisofcholesterolresultedinagentsthatinhibitedlateinthebiosyntheticpathwaybetweenlanosterolandcholesterol.Amajorrate-limitingstepinthepathwayisatthelevelofthemicrosomalenzymethatcatalyzestheconversionofHMGCoAtomevalonicacid,andthathasbeenconsideredtobeaprimetargetforpharmacologicinterventionforseveralyears.[15] HMGCoAreductaseoccursearlyinthebiosyntheticpathwayandisamongthefirstcommittedstepstocholesterolformulation.InhibitionofthisenzymecouldleadtoaccumulationofHMGCoA,awater-solubleintermediatethatis,then,capableofbeingreadilymetabolizedtosimplermolecules.Thisinhibitionofreductasewouldleadtoaccumulationoflipophylicintermediateswithaformalsterolring. LovastatinwasthefirstspecificinhibitorofHMGCoAreductasetoreceiveapprovalforthetreatmentofhypercholesterolemia.Thefirstbreakthroughineffortstofindapotent,specific,competitiveinhibitorofHMGCoAreductaseoccurredin1976,whenEndoetal.reportedthediscoveryofmevastatin,ahighlyfunctionalizedfungalmetabolite,isolatedfromculturesofPenicilliumcitrium.[40] Biosynthesis[edit] ArchitectureofthelovastatintypeIPKSsystem.Outlineddomainsareusediteratively.ACP-acylcarrierprotein,AD-alcoholdehydrogenase,AT-acyltransferase,DH-dehydratase,KS-ketoacylsynthase,KR-ketoreductase,MT-methyltransferase,ER-enoylreductase,C-condensation,TE-thioesterase.(*)-redundantdomain/inactivenotusedinthisstep. Biosynthesisoflovastatin ThebiosynthesisoflovastatinoccursviaaniterativetypeIpolyketidesynthase(PKS)pathway.ThesixgenesthatencodeenzymesthatareessentialforthebiosynthesisoflovastatinarelovB,lovC,lovA,lovD,lovG,andlovF.[41][42]ThesynthesisofdihydromonacolinLrequiresatotalof9-malonylCoa.[41]ItproceedsinthePKSpathwayuntilitreaches(E)ahexaketide,whereitundergoesaDiels-Aldercycloadditiontoformthefusedrings.AftercyclizationitcontinuesthroughthePKSpathwayuntilitreaches(I)anonaketide,whichthenundergoesreleasefromLovBthroughthethioesteraseencodedbyLovG.DihydromonacolinL,(J),thenundergoesoxidationanddehydrationviaacytochromeP450oxygenaseencodedbyLovAtoobtainmonacolinJ,(L). TheMTdomainfromlovBisactiveintheconversionof(B)to(C)whenittransfersamethylgroupfromS-adenosyl-L-methionine(SAM)tothetetraketide(C).[41]OwingtothefactthatLovBcontainsaninactiveERdomain,LovCisrequiredatspecificstepstoobtainfullyreducedproducts.ThedomainorganizationofLovB,LovC,LovGandLovFisshowninFigure2.TheinactiveERdomainoflovBisshownwithanovalandwhereLovCactsintranstoLovBisshownwitharedbox. Inaparallelpathway,thediketidesidechainoflovastatinissynthesizedbyanotherhighlyreducingtypeIpolyketidesynthaseenzymeencodedbyLovF.Lastly,thesidechain,2-methylbutyrate(M)iscovalentlyattachedtoC-8hydroxygroupofmonacolinJ(L)byatransesteraseencodedbyLovDtoformlovastatin. Totalsynthesis[edit] AmajorbulkofworkinthesynthesisoflovastatinwasdonebyM.Hiramainthe1980s.[43] [44] Hiramasynthesizedcompactinandusedoneoftheintermediatestofollowadifferentpathtogettolovastatin.Thesyntheticsequenceisshownintheschemesbelow.Theγ-lactonewassynthesizedusingYamadamethodologystartingwithglutamicacid.Lactoneopeningwasdoneusinglithiummethoxideinmethanolandthensilylationtogiveaseparablemixtureofthestartinglactoneandthesilylether.ThesilyletheronhydrogenolysisfollowedbyCollinsoxidationgavethealdehyde.Stereoselectivepreparationof(E,E)-dienewasaccomplishedbyadditionoftrans-crotylphenylsulfoneanion,followedbyquenchingwithAc2Oandsubsequentreductiveeliminationofsulfoneacetate.Condensationofthiswithlithiumanionofdimethylmethylphosphonategavecompound1.Compound2wassynthesizedasshownintheschemeinthesyntheticprocedure.Compounds1and2werethencombinedusing1.3eqsodiumhydrideinTHFfollowedbyrefluxinchlorobenzenefor82hrundernitrogentogettheenone3. Simpleorganicreactionswereusedtogettolovastatinasshowninthescheme. Cholesterolbiosyntheticpathway HMGCoAreductasereaction BiosynthesisusingDiels-Aldercatalyzedcyclization Biosynthesisusingbroadlyspecificacyltransferase Synthesisofcompounds1and2 Completelovastatinsynthesis Societyandculture[edit] Naturalsources[edit] Lovastatinisanaturallyoccurringcompoundfoundinlowconcentrationsinfoodsuchasoystermushrooms,[45]redyeastrice,[46]andPu-erh.[47] Brandnames[edit] Mevacor,Advicor(asacombinationwithniacin),Altocor,Altoprev Otherapplications[edit] Inplantphysiology,lovastatinhasoccasionallybeenusedasinhibitorofcytokininbiosynthesis.[48] Seealso[edit] Medicinalfungi References[edit] ^abcdeNeuvonen,PJ;Backman,JT;Niemi,M(2008)."Pharmacokineticcomparisonofthepotentialover-the-counterstatinssimvastatin,lovastatin,fluvastatinandpravastatin".ClinicalPharmacokinetics.47(7):463–74.doi:10.2165/00003088-200847070-00003.PMID 18563955.S2CID 11716425. ^abcdefg"LovastatinMonographforProfessionals".Drugs.com.AmericanSocietyofHealth-SystemPharmacists.Retrieved3March2019. 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Externallinks[edit] MediarelatedtoLovastatinatWikimediaCommons "Lovastatin".DrugInformationPortal.U.S.NationalLibraryofMedicine. vteLipid-modifyingagents(C10)GItractCholesterolabsorptioninhibitors,NPC1L1 Ezetimibe SCH-48461 Bileacidsequestrants/resins(LDL) Colesevelam Colestilan Colestipol Colestyramine Colextran LiverStatins(HMG-CoAreductase,LDL) Atorvastatin Cerivastatin‡ Fluvastatin Lovastatin Mevastatin Pitavastatin Pravastatin Rosuvastatin Simvastatin# Niacinandderivatives(HDLandLDL) Acipimox Aluminiumnicotinate Niacin Niceritrol Nicofuranose Nicotinylalcohol MTTPinhibitors(VLDL) Dirlotapide Lomitapide Mitratapide ATPcitratelyaseinhibitors(LDL) Bempedoicacid BloodvesselsFibrates(PPAR) Aluminiumclofibrate Bezafibrate Cholinefenofibrate Ciprofibrate Clinofibrate Clofibrate‡ Clofibride Etofibrate Fenofibrate Gemfibrozil Nafenopin Pemafibrate Ronifibrate Simfibrate CETPinhibitors(HDL) Anacetrapib† Dalcetrapib§ Evacetrapib§ Obicetrapib† Torcetrapib§ PCSK9inhibitors(LDL) Alirocumab 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