银杏叶提取物对比格犬体内西洛他唑药动学的影响

66Vol.6No.6200811ChineseJournalofPharmaceuticsNov.2008p.38620080418(1982),(),,,[e-mail];(1963),(),,,,Tel.[phone],[e-mail](2008)06038606(110016)HPLCAUC0~tCmaxtt1/2KeAUC0~∞AUC0~tCmaxR944A[1-3][4]CYP2C19CYP3A4[5]CYP2C19CYP3A4[6-7]1LC10ATSPD10ATAT130()N20006387()CenturySILC18BDS(4.6mm150mm5µm)YKH()(GBE)()()()22.1CenturySILC18BDS(150mm4.6mm5µm)(11)254nm401.0mL·min-150µL0.001AUFS2.21mL10mL(40µg·mL-1)10µL30s20g·L-1100µL3mL3min3000r·min-15min40200µL30s3min50µL2.31mL10mL0.010.020.040.080.20.512µg·mL-12.2(A/As)(C)2.41mL10mL10µL0.040.52µg·mL-1()32.22.50.040.52µg·mL-1352.253RSD5dRSD2.66(123456)3886(202.5)kg1~312h100mg4~6400mg·d-112h100mg14d20G0.511.52346812243248h4mL3000r·min-110min2033.1(A/As)(C)A/As=0.7854C+0.0043r=0.99960.012µg·mL-11/C0.040.52µg·mL-1()370.59%74.17%75.51%73.42%RSD2.54%1Table1PrecisionofthemethodforthedeterminationofcilostazolWithin-dayBetween-dayC/(µg·mL-1)MeanRSD/%MeanRSD/%0.040.0357.920.0379.770.50.5664.520.5796.1222.1110.272.088.54mean7.578.148min14min1Ablankplasma;BcilostazolandinternalstandardinplasmawithoutGBE;CcilostazolandinternalstandardinplasmawithGBEFig.1ThechromatogramsofcilostazolandinternalstandardU/mVU/mVU/mV63893.26CmaxtmaxKe(h-1)tt1/2(h)0.693/KeAUC0~tAUC0~=AUC0~t+Ct/KeCt232Table2PharmacokineticparametersinplasmaafterperoraladministrationofcilostazolwithoutGBETable3PharmacokineticparametersinplasmaafterperoraladministrationofcilostazolwithGBENo.tmax/hCmax/mg·L-1t1/2/hKe/h-1AUC0-t/(mg·h·L-1)AUC0-∞/(mg·h·L-1)131.0848.8110.07876.4756.787210.6983.2960.21021.7621.767321.0948.7290.07945.8996.076421.1119.5470.07266.9927.363511.0326.6370.10444.6134.822621.13212.5440.05525.6985.856mean1.8331.0258.2610.10915.2405.445SD0.7530.1643.0920.05791.8831.99823Ket1/2No.tmax/hCmax/mg·L-1t1/2/hKe/h-1AUC0-t/(mg·h·L-1)AUC0-∞/(mg·h·L-1)131.45621.8840.03176.5547.296210.99817.2590.04022.4783.173331.31428.6650.02426.8867.833431.22820.9300.03317.0477.599521.07713.9820.04963.5013.885631.58932.9420.02107.6668.634mean2.5001.27722.6100.03575.6896.403SD0.8370.2247.0690.00962.2812.2813906♦withGBE;◊withoutGBEFig.2Pharmacokineticprofilesofcilostazolafterperoraladministrationof100mgcilostazolwithandwithoutGBE(n=6,mean±SD)AUC0~tCmaxlnAUC0~tlnCmaxlnAUC0~tlnCmaxtt(12)4Table4Doubleone-sidetestand90%confidenceintervalanalysisresultoflnAUC0-tandlnCmaxParametersT1T290%confidenceintervallnAUC0-t1.5282.36673.4%113.9%lnCmax2.5108.63770.9%90.9%4lnAUC0~t90%73.4%~113.9%80%~125%AUC0~tlnCmax90%70.9%~90.9%70%~143%CmaxKet1/2HPLC[8][1].[J].,1999,9(4):912.C/(µg·mL-1)6391[2]BENJAMINJ,MUIRT,BRIGGSK,eta1.AcaseofcerebralhaemorrhageCanGinkgobilobabeimplicated?[J].PostgradMedJ,2001,77(904):112113.[3].[J].,2003,16(2):145146.[4]SCHRORK.Thepharmacologyofcilostazol[J].DiabetesObesMetab,2002,4(S2):1419.[5]PRASADNVT,CHAU-HWEIJF,NORMAJB,etal.Thequantitativedeterminationofcilostazolanditsfourmetabolitesinhumanlivermicrosomalincubationmixturesbyhigh-performanceliquidchromatography[J].JPharmBiomedAnal,1998,18(3):441451.[6]YINOQ,TOMLINSONB,WAYEMM,etal.Pharmacogeneticsandherb–druginteractions:experiencewithGinkgobilobaandomeprazole[J].Pharmacogenetics,2004,14(12):841850.[7]YANGXF,WANGNP,LUWH,etal.EffectsofGinkgobilobaextractandtanshinoneoncytochromeP-450isozymesandglutathionetransferaseinrats[J].ActaPharmSin,2003,24(10):10331038.[8]SUKW,WOOKK,KWOMKI.Pharmacokineticandpharmacodynamicmodelingoftheantiplateletandcardiovasculareffectsofcilostazolinhealthyhumans[J].ClinPharmacolTher,2002,71(4):246252.InfluenceofextractsoftheleavesofGinkgobilobaonthepharmacokineticsofcilostazolinBeagledogsCHENBin-bin,ZOUMei-juan,WANGChen,WANGYue,LIYan,CHENGGang(SchoolofPharmacy,ShenyangPharmaceuticalUniversity,Shenyang110016,China)Abstract:ObjectiveTostudyeffectsofextractsoftheleavesofGinkgobiloba(GBE)onthepharmacokineticsofcilostazol.MethodsTheplasmaconcentrationsofcilostazolweremeasuredbyusingavalidatedHPLCmethodwithaultravioletdetector.EffectsofGBEonthepharmacokineticparametersofcilostazolinBeagledogswerestudied.ResultsAccordingtotheevaluationstandardsofbioequiavailability,90%confidenceinterval(CI)forCmaxofcilostazolwereinthepredefinedrangeof0.71.43,the90%CIforAUC0-tandAUC0-∞wereoverlappedbutrangedtotheoutsideofthepredefinedrangeof0.81.25.TheresultsshowedthatCmaxofcilostazolwerebioequivalent,whiletheAUC0-tandAUC0-∞ofcilostazolwerenotbioequivalent.ComparedtothecilostazolcombiningGBEgroup,Keincreasedandt1/2decreasedsignificantlyinthecilostazolalonegroup.ConclusionsThestudyshowedthatGBEhasobviouseffectonthepharmacokineticparametersofcilostazolinvivo.ItissuggestedthatthedoseshouldbeadjustedappropriatelywhenGBEandcilostazolareusedtogetherinclinictopreventpotentialadverseeffects.Also,theclottingtimeshouldbemonitoredtoreducetheriskofhemorrhage.Keywords:pharmaceutics;cilostazol;Ginkgobiloba;pharmacokinetics;bioequiavailability