中南药学

’*(,,,,,(,410011):(QTP)。192。。,QTPcssmax、AUCss0～∞、t1/268%、129%、92%;Ke、Cl55%、52%;V/F。(QTP-SF)cssmax、AUCss0～∞、AUC64%、23%70%,t1/2211%。7-(QTP-H)Ke、AUC61%、45%,t1/2203%。7---(QTP-ND)cssmax、AUCss0～∞、AUC36%、40%、71%,Ke、t1/2。。CYP3A4,。:;;:R969.2:A:1672-2981(2005)04-0240-03DruginteractionbetweenquetiapineanderythromycininvivoLiKun-yan,LiHuan-de,ChengZe-neng,ZhangBi-kui,PengWen-xing,WangFeng(ClinicalPharmaceuticalResearchInstitute,XiangyaSecondHospital,CentralSouthUniversity,Changsha410011)ABSTRACT:OBJECTIVETodeterminetheeffectoferythromycinonthemetabolismofquetiapineinChineseschizo-phreniapatients.METHODSNineteenpatientsreceivedmultipledosesofquetiapine(200mg,twicedaily)withorwithoutco-administerederythromycin(500mg,threetimesdaily).Bloodsampleswerecollectedatspecificintervalsforthedeterminationofplasmaconcentrationsofquetiapineandsomeofitsmetabolites.RESULTSWitherythromy-cinco-administration,forquetiapine,cssmax,AUCss0～∞,andt1/2increasedby68%,129%and92%,respectively.ClandKedecreasedby52%and55%,respectively;forquetiapinesulfoxide(QTP-SF),cssmax,AUCss0～∞andAUCratiodecreasedby64%,23%and70%,respectively,andt1/2increasedby211%;for7-hydroxy-quetiapine(QTP-H),KeandAUCratiodecreasedby61%and45%,respectively,andt1/2increasedby203%;for7-hydroxy-N-desalkyl-quetiapine(QTP-ND),cssmax,AUCss0～∞andAUCratiodecreasedby36%,40%and71%,respectively.CONCLU-SIONSErythromycinhasanoticeableeffectonthemetabolismofquetiapine.Whenquetiapineisco-administeredwithCYP3A4inhibitorslikeerythromycin,dosingregimenshouldbemodifedaccordingtoquetiapineTDM.KEYWORDS:quetiapine;erythromycin;druyinteraction(quetiapine,QTP),[1～3]。QTPCYP3A4、O-、N-[4～5]。QTP。,,(quetiapinesulfoxide,QTP-SF),7-(7-hydroxy-quetiapine,QTP-H)7---(7-hydroxy-N-dealkyl-quetiapine,QTP-ND)[6]。[7～8]。。,(erythro-mycin,E)CYP3A4,CYP3A4,CYP3A4[9]。。:(1975～),,,Tel:[phone]E-mail:[e-mail]:(1953～),,,,Tel:[phone]Email:[e-mail]2005,Vol.3No.42005834’*!11.11.1.1AstraZeneca(London,UK),LOTAM188,20011111,3:25、100、200mg·-1;125mg·-1。,99.6%;7--、7--N-AstraZeneca;,99.9%;、(Tediacompa-ny);;(,)。1.1.2Waters2690,MicromassZQ,Masslynx3.0,SU-PELCOOasisTMHLB(1mL/100mg);();AG285(METTLERTOLEDO);(IEC,USA)。1.2。(CCMD-Ⅲ),、,、,。,18～60,1～2CYP3A4,6。、、QTP、、。。。1.3、、。1。1(mg)(7:30am)(12:00am)(7:30pm)1QTP25QTP252QTP50QTP503QTP100QTP1004～7QTP200QTP2008QTP2009～11QTP200+E500E500QTP200+E50012QTP200+E500E500E50013QTP200QTP200:QTP:;E:。1.48、12,0.25、0.5、1.0、1.5、2.0、3.0、4.0、5.0、6.0、8.0、12.0、24.0h2～3mL,,,-80℃,QTP。1.5QTP[10]KromasilC18(250mm×4.6mm,5µm),(1.70mmol·L-1,5.8mmol·L-1)-(65:35),0.95mL·min-1。(ESI+),(SIR),。QTPQTP-SF10～2000µg·L-1,QTP-H、QTP-ND1～200µg·L-1,,300、150、400、150ng·L-1(S/N=3)。85%,、RSD15%。1.6AUCss0～12、AUCss0～24,AUCss0～∞AUCss0～24+css24/Ke,Ke,Ke2.303,t1/2=0.693/Ke,cssmax,Cl=/AUCss0～12,VCl/Ke。1.7SSPS10.0,±(-x±s);,,P0.05。220023～9,21,2。19。-1。1-A.;B.。,QTPcssmax、AUCss0～∞、t1/268%、129%、92%,;Ke、Cl55%、52%,;V/F(2)。,QTP-SFcssmax、AUCss0～∞、AUC64%、23%70%,;t1/2211%,(2)。,QTP-HKe、AUC61%、45%,;cssmax、AUCss0～24,;t1/2203%,;AUCss0～∞,(2)。,QTP-NDcssmax、AUCss0～∞、AUC36%、40%、71%,;Ke、t1/2(2)。3,[7][8]。,2005834CentralSouthPharmacy.August2005,Vol.3No.4’*’,3CYP3A4。2[19,()]QTP1a2bPQTP-SF1a2bPQTP-H1a2bPQTP-ND1a2bPcmax(µg·L-1)670(314)1136(459)0.001451(216)319(177)0.00458(22)54(26)0.19819(5)12(3)0AUCss0～12(µg·h·L-1)3538(1728)6539(2213)02512(854)2080(956)0.039335(104)323(129)0.421153(44)96(32)0AUCss0～∞(µg·h·L-1)5514(4120)12649(6945)03858(2012)2981(1880)0.031529(262)677(292)0.109287(107)172(68)0t1/2(h)7.0(3.1)16.1(9.9)07.0(3.2)21.8(13.3)07.8(5.1)23.6(14.6)09.4(2.7)9.2(2.8)0.723Ke(1/h)0.11(0.03)0.05(0.02)00.11(0.03)0.04(0.02)00.10(0.03)0.04(0.02)00.08(0.02)0.08(0.03)0.725V(L)669(415)745(446)0.379Cl(L·h-1)67.2(26.6)34.3(12.5)0AUCratioc0.81(0.23)0.24(0.18)00.11(0.03)0.06(0.03)00.07(0.04)0.02(0.01)0:a.;b.;c.AUCss0～∞AUCss0～∞。:①,t1/2,,CYP3A4;②QTP-SFcssmaxAUC,QTP-SF,CYP3A4;③QTP-NDAUC、cssmaxAUCss0～∞,QTP-ND,CYP3A4N-;④QTP-HcssmaxAUCss0～∞,QTP-H,CYP3A47。QTP-HAUCAUCss0～∞。QTPCYP3A4,QTP。,,QTP。,,QTP-SFQTP-Ht1/220h,,,,,t1/27h,,3t1/2,24h。:。AstraZeneca。～～～～～～[1]McConvilleBJ,ArvanitisLA,ThyrumPT,etal.Pharmaco-kinetics,tolerability,andclinicaleffectivenessofquetiapinefu-marate:anopen-labeltrialinadolescentswithpsychoticdisor-ders[J].JClinPsychiatry,2000,61(4):252[2]ArvanitisLA,MillerBG.Multiplefixeddosesof“Seroquel”(quetiapine)inpatientswithacuteexacerbationofschizophre-nia:acomparisonwithhaloperidolandplacebo[J].BiolPsy-chiatry,1997,42(4):233[3]KingDJ.Drugtreatmentofthenegativesymptomsofschizo-phrenia[J].EurNeuropsychopharmacol,1998,8(1):33[4]NemeroffCB,KinkeadB,GoldsteinJ.Quetiapine:preclinicalstudies,pharmacokinetics,druginteractions,anddosing[J].JClinPsychiatry,2002,63(Suppl13):5[5]DeVaneCL,NemeroffCB.Clinicalpharmacokineticsofque-tiapine:anatypicalantipsychotic[J].ClinPharmacokinet,2001,40(7):509[6]GefvertO,BergstromM,LangstromB,etal.Timecourseofcentralnervousdopamine-D2and5-HT2receptorblockadeandplasmadrugconcentrationsafterdiscontinuationofquetiapine(Seroquel)inpatientswithschizophrenia[J].Psychophar-macology(Berl),1998,135(2):119[7]DevV