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DifferencesinPharmacokineticsandExVivoAntioxidantActivityFollowingIntravenousandOralAdministrationsofEmodintoRatsCHI-SHENGSHIA,1YU-CHIHOU,2SHANG-YUANTSAI,2PEI-HSUNHUIEH,3YANN-LIILEU,4PEI-DAWNLEECHAO21234InstituteofPharmaceuticalChemistry,ChinaMedicalUniversity,40402Taichung,TaiwanSchoolofPharmacy,ChinaMedicalUniversity,40402Taichung,TaiwanInstituteofChinesePharmaceuticalSciences,ChinaMedicalUniversity,40402Taichung,TaiwanGraduateInstituteofNaturalProducts,ChangGungUniversity,33302Kweishan,Taoyuan,TaiwanReceived18April2009;revised10September2009;accepted12September2009Publishedonline17November2009inWileyInterScience().DOI10.1002/jps.21978ABSTRACT:Emodin,anaturalanthraquinonepolyphenol,hasbeenreportedtopossesspromisinginvitroantioxidation,anticancerandanti-inflrtheinvitrobioactivitiescanpredictinvivoeffectsremainedanunanswfillthisblank,wasintravenously(5.0mg/kg)andorally(20.0and40.0mg/kg)ampleswereassayservedthatafterintravenousbolusofemodin,theparentformofemodindeclinedrapidly,andemodinglucuronides,v-hydroxyemodin(v-OHE)andv-OHEsulfates/rast,whenemodinwasgivenorally,emodinglucuronideswereexclusivelypresentinserum,whereasemodin,v-OHEandv-OHEsulfates/rtoevaluatetheinvivoantiox-idationactivity,theserummetabolitesofemodinfollowingintravenousandoraladministrationswerepreparedfromratsandcharacterized,followedbyinvestigatingtheeffectson2,20-azobis(2-amidinopropanehydrochloride)-ultssuggestedthattheserummetabolitesoforalemodinexhibitedmorepromisingfreeradicalscestbiologiststoredirecttheirtargetstoemodinglucuronide.ß2009Wiley-Liss,AmericanPharmacistsAssociationJPharmSci99:2185–2195,2010Keywords:emodin;v-hydroxyemodin;pharmacokinetics;metabolism;glucuronidesINTRODUCTIONEmodinisananthraquinonepolyphenoldistrib-utedinseveralpopularChineseherbpondenceto:Pei-DawnLeeChao(Telephone:886-4-22031028;Fax:886-4-22031028;E-mail:pdlchao@)JournalofPharmaceuticalSciences,Vol.99,2185–2195(2010)ß2009Wiley-Liss,AmericanPharmacistsAssociationrhizomesofRheumpalmatumL.,,Rheumoffisinvitrobeneficialactivitiesofemodin,includingantioxidation,1,2anti-inflammation,3,4anti-angio-genesis5,6andanticancer7–r,whethertheinvitrofindingscanpredictinvivoeffectsofemodinremainedanunansweredquestionforthelackofunderstandingthemetabolismandpharmacokineticsofemodininanimals.2185JOURNALOFPHARMACEUTICALSCIENCES,VOL.99,NO.4,APRIL2010

Inrecentyears,variousstudieshaveshownthatflavonoidpolyphenolsareoftensubjectedtoextensiveconjugationmetabolismduringthefirstpassthroughgut/liverandthefreeformsweregenerallynotpresentinthecieculation.13–15Apreviousstudyhasreportedverypoororalbioavailabilityofemodininrabbits.16Inregardtothemetabolicfateofemodin,severalinvitrometabolitessuchasemodicacid,physcion,2-hydroxyemodin,4-hydroxyemodin,5-hydroxye-modin,7-hydroxyemodinandv-hydroxyemodin(v-OHE,chemicalstructureshowninFig.1),havebeenidentifiedbyusinghepaticmicrosomes.17,18However,limitedinformationisavailablecon-eendtofillthisblank,thisstudyinvestigatedthemetabo-lism,epasttwodecades,thefreeradical-mediatedperoxidationofmembranelipidandoxidativedamageofDNAwasbelievedtobeassociatedwithavarietyofhealthproblems,suchascancer,atherosclerosis,usstudieshavereportedpromisinginvitroantioxidationactivityofemodin,1,2nevertheless,theinvitroeffitensionofourpharmacokineticstudy,theserummeta-bolitesofemodinafterintravrtoevaluatetheinvivofreeradicalscavengingactivityofemodin,anexvivoassayoftheserummetabolitesofemodinagainst2,20-azobis(2-amidinopropanehydrochlor-ide)(AAPH)-inducedhemolysiswasconducted.H-1,fromHelixpomotia,containing14,000units/gofsulfataseand498,800units/gofb-glucuroni-dase)werepurchasedfromSigmaChemicalCo.(,MO).2-Methylanthraquinoneand2,20-azobis(2-amidinopropanehydrochloride)(AAPH,97%).(Milwaukee,WI).v-Hydroxyemodin(v-OHE)wasisolatedandidentifiedbyoneoftheauthors,itrile,methanolandethylacetatewereLCgradeandpurchasedfromMallinckrodtBaker,Inc.(Phillipsburg,NJ).L(þ)-AscorbicacidwasobtainedfromRdHLaborche-mikalienGmbH&(Seelze,Germany).-Qpluswater(Millipore,Bedford,MA)ministrationandBloodCollectionMaleSprague-Dawleyratsweighing300–350gwerefastedfor15hbeforeravenousbolus,emodinwasdissolvedinPEG400,filteredthrougha0.22mmmembraneandgiventosixratsviatailveinatadoseof5.0mg/1.0mL/ampleswerewithdrawnbeforedosingandat5,15,45,90,180,300,480,ladministration,emodinwasalsodissolvedinPEG400andgivenviagastricgavageatdosesof20.0and40.0mg/8.0mL/amples(0.8mL)werewith-drawnbeforedosingandat10,30,60,120,240,480,720,1440,2880,odsampleswerecentrifugedat10,000gfor15minandtheserumobtainedwerestoredatÀmalstudyadheredto‘‘TheGuidebookfortheCareandUseofLaboratoryAnimals(2002)’’(PublishedbytheChineseSocietyfortheLaboratoryAnimalScience,MATERIALSANDMETHODSChemicalsEmodin(purity98%),PEG400,b-glucuronidase(TypeB-1,frombovineliver)andsulfatase(Type

Taiwan,ROC).TheprotocolwasapprovedbytheCommitteeofAnimalManagement,ChinaMedicalUniversity,Taichung,terizationoftheMetabolitesofEmodinbyLC/MSInordertocharacterizeemodinglucuronidesandv-OHEsulfates/glucuronides,LC/MSchromato-gramsofserumsamplebeforrolysisreactions,thesulfatase(1000unil/mL)inusecontainedintrinsically35,628units/(100mL)asmixedwith100mLofb-glucuronidase(1000units/mLinpH5acetatebuffer),or100mLofsulfatase(1000units/mLinpH5acetatebuffer,containing35,628units/mLofb-glucuronidase).Acetatebuf-fer(pH5)eof50mLofascorbicacid(100mg/mL)wasadded,whichcanpreventtheoxidativedecayofanthraquinonefreeforms,andiumsampleswithandwithernatantwasevaporatedunderN2gastodrynessandreconstitutedwith20mLofmethanol,andthen2mLwassubjecttoLC//MSsystemconsistedofaShimadzuLC-20ADHPLCseriesliquidchromatographandaShimadzuLC–MS2010EVsinglequadrupolemassspectrometer,whichwasequippedwithanelectrosprayionization(ESI)rationforemodinglucuronideswasachievedusingaLunaC18column(150mmÂ1.0mm,5mm,Phenomenex)withanisocraticmobilephaseconsistingofacetonitrileand0.1%formicacid(40:60,v/v),whereasgradientelutionwasemployedforv-OHEsulfates/glucuronides:A/B:10/90(0–10min),30/70(15–20min),60/40(25–30min),80/20(40–50min),and10/90(60–70min).Theflowrateswere0.1mL/minandtheefflvedissolutionline(CDL)tempera-tureandtheblocktemperatureweremaintainedat250and2008C,bevoltage(capillaryvoltage),CDLvoltageanddetectorvoltagewerefixedat4.5kV,À5V,and1.5kV,DOI10.1002/wasobtainedbyaTurbomolecularpump(Edwards28,UK).Liquidnitro-genwasusedasthesourceofnebulizergas(1.5L/min).Analyseswereperformedinselectedionmonitoring(SIM)modewith[m/zÀH]¼269foremodin,445foremodinglucuronides,285forv-OHE,tationofEmodin,v-OHE,andTheirConjugatedMetabolitesinSerumFortheassayoftheparentformsofemodinandv-OHE,100mLofserumwasmixedwith100mLofpH5acetatebufferand50mLofascorbicacid(100mg/mL),then100mLof0.1NHClwasaddedandpartitionedwith350mLofethylacetate(containing1mg/mLof2-methylanthraquinoneasaninternalstandard).TheethylacetatelayerwasevaporatedunderN2gastodrynessandreconstitutedwith50mLofthemobilephase,quantitationoftheglucuronidesofemodinandv-OHE,100mLofserumwasmixedwith100mLofb-glucuronidase(1000units/mLinpH5acetatebuffer)and50mLofascorbicacid(100mg/mL).Themixturquantitationofthesulfatesofemodinandv-OHE,100mLofserumwasmixedwith100mLofsulfatase(1000units/mLinpH5acetatebuffer,containing35,628units/mLofb-glucuro-nidase),50mLofascorbicacid(100mg/mL)nzymatichydrolysis,serumsamplesweresubjectedtotheson-siderableamountofb-glucuronidasecontainedinsulfataseTypeH-1,theaglyconesreferencebetweentreatmentswibratorpreparation,100mLofserumspikedwithvaribrationcurvewasdrawnbylinearregressionofthepeakarearatios(emodinandv-OHEtointernalstandard)LOFPHARMACEUTICALSCIENCES,VOL.99,NO.4,APRIL2010

nditionsfortheAnalysisofEmodinandv-OHEinSerumTheHPLCapparatusincludedapump(LC-10AT,Shimadzu,Kyoto,Japan),anUVdetector(SPD-10AVP,Shimadzu,Kyoto,Japan)andanauto-maticinjector(Series200Autosampler,PerkinElmer,Norwalk,CT).TheCosmosil5C18-ARIIcolumn(4.0Â250mm,5mm)wasequippedwithaguardcolumn(4.6Â50mm,5mm)(GLScienceInc.,Tokyo,Japan).Theisocraticmobilephaseconsistedofacetonitrileand0.1%phosphoricacidataratioof61:39(v/v).flowratewas1.0mL/tionofAssayMethodforSerumThesyscisionwasanalyzedbyintradayandinterdauracyofthesystemwasexpressedbytherelativeerrorofthemeriesweremeasuredbyspikingemodinandv-OHEintoblankserumandwaterintriplicatestoafford10.0,20.0,40.0mg/mLand1.25,2.5,5.0mg/mL,respectively,andtheconcentrationQ(lowerlimitofquantitation)representsthelowestconcentrationofanalyteinasamplethatcanbedeterminedwithacceptableprecisionandaccuracy,whereasLOD(limitofdetection)representsthelowestconcentrationofanalysisinasamplethatcanbedetected(withsignal/noise>3).EffectsofEmodin,ItsIntravenousandOralMetabolitesonAAPH-InducedHemolysis19Inordertoevaluatetheinvivoantioxidanteffectofemodininsystemiccirculation,anexvivoassayoftheserummetaborague-Dawleyratsineachgroupwerefastedfor12hand5mLofbloodwaswithdrawnfromeachratat10minafteranintravenousbolusof5mg/kgofemodinandafteroraladministrationof20mg/umobtainedemovingtheprecipi-JOURNALOFPHARMACEUTICALSCIENCES,VOL.99,NO.4,APRIL2010tatesandfollowedbyevaporatingmethanolundervacuum,theresiduewasdissolvedwithwaterandsubjectedtosolidphaseextraction(SPE)usingStrata1(Phenomenex,Torrance,CA)eoussolutionsofserummeta-boliteswerelyophilizedtoobtainpowdersandstoredatÀ808C,ofwhichanaliquotwrthreeSprague-Dawleyratswerefastedovernight,10mLofbloodwaswitemovingplasmaandbuffycoat,erythrocyteswerewashed5timeswithtwofoldvolumeofcoldphosphate-bufferedsaline(PBS).Duringthelastwash,theerythrocy100mLoferythrocytesuspension,100mLof100mMAAPH(inPBS)and200mLofPBScontainingvariousconcentrationsofemodinanditsserummetaboliteswereadded.L-Asctionmixturewasshakengentlyandincubatedat378Cfor0,1,3,5,7,ncubation,thereactionmixturewasaddedwithanequalvolumeofphosphatebufferedsaline(PBS)andcentrifugedat10,,centageofhemolysisatdifferentincubationintervalswasdeterminedbymeasioxidantactivitywasdefinedasthepercentdecreaseoftheslopeofhemolysis–timecurvecalculatedbylinearleastsquaresregression(r>0.95),alysisThepeakserumconcentration(Cmax)andthetimetopeakconcentration(Tmax)rmacokineticparameterswereanalyzedbynoncompartmentmethodwiththeaidoftheprogramWINNONLIN(version1.1SCIsoftware,StatisticalConsulting,Inc.,Apex,NC).Theareaundertheserumconcentration–timecurve(AUC0–t)ectsonAAPH-inducedhemolysisamongvarioustreatmentsDOI10.1002/jps

EMODINPHARMACOKINETICS2189werestatisticallycomparedusingANOVAwithTukey’SCharacterizationofMetabolitesafterIntravenousBolusofEmodinbyLC/MSTheleftpanelofFigure2ashowstwodistinctpeakswithm/z445and269of[MÀH]Àelutedat3.5and17.5min,ydrolysiswithb-glucuronidase,thepeakwithm/z445disappeared,andresultedinamarkedenhance-mentofthepeakwithm/z269asshownintherightpanel,suggestingthatthepeakwithm/2bshowsthechromatogramsofaserumsamplebeforeandafterhydrolysiswithsulfatase/b-glucuronidaseandb-glucuronidase,arisonwiththeretentiontimeandmassspectrumofanauthenticstandard,thepeakwithm/z285wasidentifiedasv-OHE,whichwasfoundmark-edlyenhancedafterhydrolysiswithsulfatase/b-glucuronidaseandb-glucuronidaseasshowninthemiddleandrightpanels,kswithm/z365and461,whichwereputativesulfateandglucuronideofv-OHE,respectively,etheserumafteroralemodincontainedalmostexclusivelyemodinglucuronides,tationofEmodinandv-OHEinSerumForthequantitationofemodinandv-OHEinserum,goodlinearrelationshipswerefoundintherangeof0.3–80.0mg/mL(y¼0.303xÀ0.040,r¼0.999)and0.6–10.0mg/mL(y¼0.328xÀ0.016,omatogramsofemodin([m/zÀH]À¼269),emodinglucuronide([m/zÀH]À¼445)(a)andv-OHE,([m/zÀH]À¼285),v-OHEglucuronide([m/zÀH]À¼461),v-OHEsulfate([m/zÀH]À¼365)(b)inaserumsampleobtained10minafterintravenousbolusofemodintoratsbefore(leftpanel)andafterhydrolysiswithglucuronidase(rightpanel)andsulfatase/glucuronidase(middlepanel).DOI10.1002/jpsJOURNALOFPHARMACEUTICALSCIENCES,VOL.99,NO.4,APRIL2010

r¼0.999),cisionandaccu-racyofthemethodindicatedthatallcoefficientsofvariation(CVs)werebelow17%andtherelativeerrorswerebelow20%.TheLLOQandLODofemodinwere0.3and0.01mg/mL,overiesofemodinfromserumwere107.0%,99.7%,and104.7%at10.0,20.0,and40.0mg/mL,QandLODofv-OHEwere0.6and0.06mg/mL,overiesofv-OHEwere100.1%,91.5%,and104.1%at1.25,2.5,and5.0mg/mL,cokineticsofEmodininRatsafterIntravenousandOralAdministrationsFollowinganintravenousbolusofemodin,themeanserumconcentration–timeprofilesofemo-din,emodinsulfates/glucuronidesandemodinglucuronidesareshowninFigure3a,thoseofv-OHE,v-OHEsulfates,fates/glucur-onidesofemodinandsulfates/filesofemodinsulfates/glucuronidesandemodinglucuronideswerelargelysuperposableandtheywerefv-OHEfreeformwasdetectedwithin30minafterdoing,whereasv-OHEglucuronidesandv-OHEsulfates/glucuronidescanbedetectedtill90and180min,centrationsofv-OHEsulfates/gluc0–720ofemodinsulfates/glucuronideswascomparablewiththatofemodinglucuronides,tion,theCmaxandAUC0–720ofv-OHEsulfates/glucuronideswere2.5-and3.4-foldofv-OHEglucuronides,temicexposureofthetotalemodin,includingfreeformandsulfates/glucuronides,nresidencetimesofemodinsulfates/glucuronidesweresignificantlylongerthanthoseofemodin,v-OHE,andv-OHEsulfates/raladministrationofemodin,traceofemodinwasdetectedattheveryearlyphase,butallbelowLLOQ,whereasemodinsulfates/glucur-onidesemergedrapidlyandreachthefi4aandbdepictstheprofilesofemodinsulfates/glucuronidesandemodinglucuronidesafteroraladministrationsof20and40mg/kgofemodin,filesofemodinglucuronidesandemodinsulfates/glucuronirmacokineticparametersarelistedinTable2,showingtheAUC0–4320ofemodinsulfates/gsofEmodin,ItsIntravenousandOralMetabolitesonAAPH-InducedHemolysisTheserummetaboliteafterintravenousadmin-istrationofemodintoratswasanalyzedafter

cokineticParametersofEmodin(E),EmodinSulfates/Glucuronides(ES/G),EmodinGlucuronides(EG),v-HydroxyemodinSulfates(v-OHES),andv-HydroxyemodinGlucuronides(v-OHEG)afterIntravenousBolusofEmodin(5.0mg/kg)toSixRatsParametersTmaxCmaxAUC0–720MRTE——378.8Æ25.9a7.7Æ0.4aES/G15.0Æ6.329.4Æ12.22014.1Æ297.4b92.2Æ14.6bEG8.3Æ2.128.6Æ2.52179.2Æ135.7b111.4Æ14.5bv-OHES8.3Æ2.113.4Æ2.7596.7Æ139.7a35.6Æ6.8v-OHEG8.3Æ2.18.1Æ0.7261.1Æ45.0b21.8Æ2.3ValuesaremeansÆnarowwithoutacommonsuperscriptdifferatpintravenousmeta-bolites)emodin,SIONTheserumconcentrationsofemodinandv-OHEwereassayedbyanHPLCmethoddevelopedpreviouslyinourlaboratorywithminormodifica-tion.18Intermsofprecision,accuracy,andrecovery,heunavailabilityofauthenticJOURNALOFPHARMACEUTICALSCIENCES,VOL.99,NO.4,(ÆSE)serumconcentration—timeprofilesofemodinS/G(*)andemodinG(5)afteroraladministrationof20.0mg/kg(a)and40.0mg/kg(b)10.1002/jps

cokineticParametersofEmodinSulfates/Glucuronides(ES/G)andEmodinGlucuronides(EG)afterOralAdministrationofEmodin(20,40mg/kg)toSixRats20mg/kgParametersTmaxCmaxAUC0–4320MRTES/G1161.7Æ548.010.0Æ1.011,489.7Æ3391.81206.1Æ297.5EG605.0Æ461.410.1Æ0.813,107.7Æ2812.11242.6Æ276.4ES/G821.7Æ429.216.6Æ1.822,703.7Æ4423.01406.2Æ269.440mg/kgEG1300.0Æ507.615.6Æ1.519,880.7Æ2168.51371.6Æ252.9ValuesaremeansÆ(min):(nmolmLÀ1):0–4320(nmolminmLÀ1):areaundertheserumconcentration–(min):rdsofthesulfatesandglucuronidesofemodinandv-OHE,rtodefineadequateserumprofilesofboththeparentformsandconjugatedmetabolitesofemodinandv-OHE,,supplementedwatertoratsviagavagetoavoidhypovolumicshockduringthefisofvarioustreatmentsonAAPH-inducedhemolysis.(a)Intravenous(i.v.)metabolitescontainingemodinG/v-OHES/v-OHEG(4:1.6:1),(b)oral(po)meta-bolitescontainingcomparableconcentrationsofemodinG,(c)emodin,and(d)LOFPHARMACEUTICALSCIENCES,VOL.99,NO.4,APRIL2010DOI10.1002/jps

isonoftheantioxidantactivityamongemodin,etabolitesofemodincontainingcomparableconcentrationsofemodinGonAPPH-inducedhemolysis.ÃÃÃp<0.001,ÃÃp<0.01,Ãp

6-rytoemodin,sulfationappearedapreferredconjuga-tionreactiontothev-alcoholgroupofv-OHE,whichwasdifsentstudyfoundthatemodinglucur-onideswerethemajormoleculesinbloodafteroraladministrationofemodin,whereasemodinglucuronides,v-OHEandv-OHEsulfates/hatpreviousinvitrostudiesreportingbeneficialbioactivitiesofemodinallfocusedonemodinparentform,1–12wethereforesuspectstingly,asanextensionofourpharmacokineticstudy,wefoundthattheeffectsofintravenousandoralmetabolitesrasttothelipophilicpropertiesofemodin,themajormetabolisentresultwasingoodagreementwithapreviousstudyreportingthatrelativelyhydro-philicpolyphenolhadhigherinhibitoryeffectonAAPH-inducedhemolysisthanrelevanthydro-phobicderivative.26Therefore,emodinglucuro-nidaringtheanti-hemolysiseffectsofintravenousandoralmetabolites,wespeculatedthatv-OHEsingtoaliterature,v-OHEsulfatesmightundergolossofHSOÀcarbocation,4,resultinginareactiveelectrophilicwhichcovalentlybondedtocellularmacromole-cules,andmayexplainthemembranedamageoferythrocytes.27Apreviousstudyhasreportedthatquercetin3-glucuronide(Q3GA)wasmoreeffectivethanquercetinaglyconeintheinhibitionofH2OÀinducedintracellularROSproductioninmouse2fibroblastculturedcells,althoughlittleQ3GAdiffusedintothecytoplasmorcellnucleuscompartment.28Inaddition,anotherstudydemonstratedthattheconjugatedmetabolitesofmorinwas1000-foldmorepotentthanmorinparentforminanti-inflammationactivity.29Theseresultsaredefinitelyinfavoroftheconclusionth,itisofmuchinteresttouLOFPHARMACEUTICALSCIENCES,VOL.99,NO.4,APRIL2010Inconclusion,entmetabolieradicalscaven-gingeffectoforalmetabolitesofemodinwasmorepromisingthantheintravenousmetabolites,nderstandingoftheinvivovirtualeffectofemodin,investigationonthebioarkwaspartlysupportedbytheNationalScienceCouncil,95-2320-B039-023-MY2,NSC96-2320-B-039-037-MY3),CommitteeonChineseMedicineandPharmacy,ROC(CCMP93-RD-006,CCMP95-TP-027),andChinaMedicalUniversity,ROC(CMU95-082,CMU95-225).S,YehSF,ofanthra-quinonederivativesonlipidperoxidationinratheartmitochondria:od58:1365–F,D´ıazY,idantandscavengingactivityofemodin,aloe-emodin,iol42:342–,ChenHL,LiH,ZhangKL,ChenXY,WangXW,KongQY,toryeffectsofemodinonNF-kBactivationandinfllMed16:41–,TuX,LinG,XiaH,HuangH,WanJ,ChengZ,LiuM,ChenG,-mediatedprotectionfromacutemyocardialinfarctionviainhibitionofinfli81:1332–,ZhangJ,-cerBiotherRadiopharm23:222–,HeMF,MaSC,pharmacol121:313–,ShenHM,toryeffectofemodinontumorinvmPharmacol68:361–10.1002/jps

,ShenHM,ShuiG,WenkMR,inhibitstumorcelladhesionthroughdisrRes66:5807–,LuG,ShenHM,ChungMC,Rev27:609–asG,BabykuttyS,SathiadevanPP,larmechanismofemodinaction:Rev27:591–,ChangHL,ShyueSK,inducesapoptosisinhumanlungadeno-carcinomacellsthroumPharmacol70:229–haczC,SuE,KolanderJ,entialinhibitionofmatrixmetalloprotei-nases-2,-9,Med75:327–rSO,StopperH,ns-formationoftheanthraquinonesamodinandchrysophtabDisposition26:540–,TsaiSY,KuoSC,HouYC,lismandpharmacokineticsof3,30,40,7-tetrahydroxyflavone(fisetin),5-hydroxyflavone,and7-hydroxyflavoneandanti-hemolysiseffectsoffiFoodChem57:83–,OpinDrugMetabToxicol3:389–W,HsiuSL,WuPP,Med61:406–T,HaraikawaK,MorookaN,NakanoS,UenoY.1985.2-Hydroxyemodin,es149:327–,XuF,ZhangZ,LiuY,DongH,uralelucidationofinvitromChromatogr22:1230–,HoltRR,LazarusSA,OrozcoTJ,toryeffectsofcocoaflavanolsandpro-DOI10.1002/jpsEMODINPHARMACOKINETICSlMed227:321–,ZhouSY,YangRT,LiuXY,LiuRW,YangX,ZhangBL,YangJY,CaoDY,tationassayforabsorptionandfirst-passmetabolismofemodininisolatedratarmBull30:1628–rJPE,ChowrimootooG,ChoudhuryR,DebnamES,SraiSK,llintestinecanbothabsorbandglucuronidateluminalfltt458:224–,Radominska-PandyaA,sonthesubstratespecifitabDisposition27:1165–,RiosGR,GreenMD,ugMetab1:143–nD,CarrierJS,ChouinardS,tabDisposi-tion31:670–,atespecificitiesoftwostablyexprtabDisposition21:50–waS,SugiyamaY,-toryeffectsofcatecholderivativesonhydrophilicfreeradarmBull44:881–,DratterJ,WangC,TungeJA,ficationofsulfationsitesofmetabolitesandpredictionofthecompounds’oanalChem386:666–M,YamanishiR,MoonJH,MurotaK,ofquercetinanditsconjugatedmetaboliteonthehydrogenperoxide-inducedintra-cellularproductionofreactiveoxygenspeciesinmousefiBiotechnolBiochem66:1015–,HouYC,ChangWC,HsiuSL,LeeChaoPD,ulfates/glucuronidesexertanti-inflammatoryactii74:743–LOFPHARMACEUTICALSCIENCES,VOL.99,NO.4,APRIL2010