[生物医药论文精品]头孢克洛干混悬剂的药动学及生物等效性研究

1头孢克洛干混悬剂的药动学及生物等效性研究A1A0A1A0A0A4A4A5A2A5A2A3A6A7A8A9A10A11A12A13A14A15A16A17A18A19A20A21A22A23A18A19A24A25A26A27A28A29A30A21A31A32A33A34A35A36A37A38A3920A40A41A42A43A44A45A46A47A48A49A50A51A52A53A54A55A56A57A58A59A60A61A49250MGA62A63A64A65A66A67A68A69A70A67A71A72A73A74A75A76A55A56A57A58A77A78A79A62A8020A40A81A82A47A77A83A84A74A85A78A79A86A87DASA88VER10A89A90A91A62A92A93A94A95A96A97A98A99A100A101A102A103A104A105A106A107A108A109A110A111A102A112A113A114A115A116A117CMAXA118A119A120A121900A122168A123A124A121959A122161A123GML1A125TMAXA118A119A120A121037A122012A123A124A121035A122005A123HA125T1/2A118A119A121088A122016A123A124A121087A122011A123HA125AUC05HA118A119A120A121791A122100A123A124A121791A122110A123GHML1A125AUC0A126A118A119A120A121798A122102A123A124A121798A122111A123GHML1A125TMAXA127A128A129A130A131A132A124A133A134A125CMAXA135AUC05HA135AUC0A126A136A137A131A138A139A140A141A142A143A118A144A125A145A136A146A147A148A149TA133A134A150A151A152A153A154TMAXA135CMAXA135AUC05HA135AUC0A126A155A156A157A158A159A143A160A125A161A162A152A153A154AUC05HA135AUC0A126A15490A163A164A165A166A167A130A168A152A153A15480A169125A170A171A172A150CMAXA15490A163A164A165A166A167A130A168A152A153A15470A169143A170A171A172A173A162A134A152A153A154A174A137A175A176A177A178A179A120A1211007A122125A123A173A180A180A181A182A183A184A185A186A187A188A184A185A189A190A191A192A193A194A195A196A197A198A199A197A198A200A201A202A203A204A205A206A207A185A204A208A209A210A211A212A213A214A215A210A211A216A217A218A215A219A220A221A215A222A217A223A224A225A226A227A228A229A226A230PHARMACOKINETICPROPERTIESANDBIOEQUIVALENCEOFCEFACLORFORSUSPENSIONAFTERSINGLEDOSEADMINISTRATIONINHEALTHYVOLUNTEERSABSTRACTA231AIMTOSTUDYTHEBIOEQUIVALENCEANDRELATIVEBIOAVAILABILITYOFTWOCEFACLORFORSUSPENSIONSMETHODSASINGLEORALADMINSTRATIONOF250MGTESTANDREFERENCESUSPENSIONSWEREGIVENTO20HEALTHYMALEVOLUNTEERSACCORDINGTOARANDOMIZEDCROSSOVERDESIGNTHECONCENTRATIONSOFCEFACLORINPLASMAWEREDETERMINEDBYAHPLC/MS/MSMETHODTHEPHARMACOKINETICPARAMETERSWERECALCULATEDANDTHEBIOEQUIVALENCEWERECOMPAREDBYDASVER10PROGRAMRESULTSTHEPHARMACOKINETICPARAMETERSOFTESTANDREFERENCEPREPARATIONSWEREASFOLLOWSCMAXWERE900A232168AND959A232161GML1A233TMAXWERE037A232012AND035A232005HA233T1/2WERE088A232016AND087A232011HA233AUC05HWERE791A232100AND791A232110GHML1A233AUC0A234WERE798A232102AND798A232111,RESPECTIVELYTHEREWERENOSIGNIFICANTDIFFERENCESP005INTMAX,CMAX,AUC05H,AUC0A234ANDT1/2BETWEENTHETWOPREPARATIONSTHERELATIVEBIOAVAILABILITYOFTESTSUSPENSIONSWAS1007A232125CONCLUSIONTHETESTANDREFERENCEPREPARATIONSWEREBIOEQUIVALENCEKEYWORDSCEFACLOR,SUSPENSION,RELATIVEBIOAVAILABILITY,BIOEQUIVALENCE,PHARMACOKINETICS,HPLC/MS/MSCEFACLORCEF,3CHLORO7D2PHENYLGLYCINAMIDO3CEPHEM4CARBOXYLICACID,ISASEMISYNTHETICCEPHALOSPORINANTIBIOTICDERIVEDFROMCEPHALEXINITDIFFERSFROMCEPHALEXINONLYINTHESUBSTITUTIONOFACHLORINEFORTHEMETHYLGROUPINTHE3POSITION,BUTEXHIBITSIMPROVEDANTIBACTERIALACTIVITYAGAINSTSTREPTOCOCCUSPNEUMONIAE,ESCHERICHIACOLI,KLEBSIELLAPNEUMONIAE,HAEMOPHILUSINFLUENZAE,ANDMOSTENTERICPATHOGENS,ANDSOITHASCOMMONLYUSEDFORTREATMENTOFINFECTIONSCAUSEDBYGRAMPOSITIVEANDGRAMNEGATIVEBACILLIBECAUSEOFITSHIGHERPOTENCY,BROADERSPECTRA,ANDBEINGABLETOBETAKENORALLY,VARIOUSFORMULATIONSOFCEFACLORHAVEBEENDEVELOPEDANDAPPROVEDTHECEFFORSUSPENSIONISOFGOODTASTESANDISTOIMPROVECOMPLIANCEOFTHECHILDRENHAVINGINFECTIOUSDISEASESWHENTHEYTAKETHESEDRUGSSEVERALTECHNIQUES13HAVEBEENREPORTEDFORCEFQUANTIFICATIONINPLASMASAMPLESFOREXAMPLE,THEHIGHPERFORMANCELIQUIDCHROMATOGRAPHYMETHODSWERENOTSATISFACTORYWITHRESPECTTOSENSITIVITY,FEASIBILITYANDRELIABILITYANDWERETEDIOUSINSAMPLEPREPARATIONINORDERTOPROVIDE2MOREGUIDANCETOTHEREASONABLEUSEOFTHISDRUG,TOSTUDYTHEPHARMACOKINETICS,AMORESENSITIVEANDSIMPLEHPLCMS/MSMETHODWASREPORTEDINTHISPAPERTHECONDITIONWITHATOTALRUNTIMEOFLESSTHAN20MIN,ISALLOWEDHIGHTHROUGHPUTDETERMINATIONOFANALYTESINCOMPLEXBIOLOGICALMATRIXESSOBASEDONOURMETHOD,THEPHARMACOKINETICSANDTHERELATIVEBIOAVAILABILITYOFCEFFORSUSPENSIONWERESTUDIEDBYUSINGBLOODSAMPLESOF20HEALTHYMALEVOLUNTEERSAFTERASINGLEORALDOSEOF250MGINARANDOMIZEDCROSSOVERDESIGN1MATERIALSANDMETHODS11INSTRUMENTSANDREAGENTSTHEAPI4000TRIPLEQUADRUPOLELC/MS/MSMASSSPECTROMETERANDAGILENT1100SYSTEMWEREUSEDTOSEPARATEANDDETECTCEFINHUMANPLASMAANALYSTSOFTWARE,VER14ABISCIEXWASUSEDTOACQUIREANDPROCESSEALLTHEDATAAG135METTLERTOLEDOSCALE,TDL16GBHIGHSPEEDCENTRIFUGE,ZH2VORTEXMIXER,ANDSB3200SUPERWAVECLEANERWEREUSEDTESTDRUGCEFFORSUSPENSION,EACHCONTAINS125MGCEF,MADEBYSHIJIAZHUANGNO4PHARMACEUTICALCO,LTD,LOTNO060215REFERENCEDRUGCEFFORSUSPENSIONCECLOR,EACHCONTAINS125MGCEF,MADEBYLILLYSUZHOUPHARMACEUTICALCO,LTD,LOTNO051013CEFSTANDARDCONTENTWAS937,LOTNO130481200503WASSUPPLIEDBYCHINESEDRUGANDBIOLOGICALPRODUCTSQUALITYCONTROLINSTITUTE,ANDPIDOTIMODSTANDARDIS,CONTENTWAS991,LOTNO010626WASPROVIDEDBYHEBEIINSTITUTEFORDRUGCONTROL,RESPECTIVELYMETHANOLANDACETONITRILEWEREALLOFHPLCGRADE,ANDOTHERREAGENTSWEREOFANALYTICALGRADE12CONDITIONSFORMASSSPECTRAANDCHROMATOGRAMTHEHIGHPERFORMANCELIQUIDCHROMATOGRAPHYSYSTEMCONSISTEDOFAGILENT1100QUATPUMP,AUTOSAMPLER,VACUUMDEGASSERAGILENT,USATHEANALYTICALCOLUMNWASALLUREC185M,46MM50MMPROCEEDEDBYPHENOMENEXC185M,430MMTHECOLUMNTEMPERATUREWASMAINTAINEDAT20THEMOBILEPHASECONSISTEDOFAMIXTUREOF20ACETONITRILAND80WATERCONTAINING1FORMICACID,ANDWASFRESHLYPREPAREDFOREACHRUNTHEFLOWRATEWAS05MLMIN1ANDTHEINJECTIONVOLUMEWAS10LTHEAPI4000TRIPLEQUADRUPLEMASSSPECTROMETERABI,CA,USAWASEQUIPPEDINMULTIPLEREACTIONMONITORINGMRMSCANMODEUSINGTURBOIONSPRAYIONIZATIONESISOURCETHESPRAYERVOLTAGEISANDVAPORIZERTEMPERATUREWERESETAT55KVAND500THEGS1ANDGS2OFNEBULIZERGASNEBWERESETAT60LMIN1AND40LMIN1THECURTAINGASCUR,ANDCOLLISIONGASCADWERESETAT15LMIN1AND8LMIN1,RESPECTIVELYTHECIDVOLTAGEWERESETAT25VFORCEFAND21VFORISTHEIONIZATIONSWEREPERFORMEDINPOSITIVEMODEMHANDTHEANALYTESWEREDETECTEDBYMONITORINGTHEFOLLOWINGIONTRANSITIONSANDTHEM/ZOFIONSSELECTEDFORQUANTITATIONWERE36801741CEFAND24521340IS13METHODSOFDISPOSALASTOCKSOLUTIONOFCEF10MGML1WASPREPAREDINWATERCONTAINING5ACETICACIDANDDILUTEDWITHBLANKPLASMACONTAINING5ACETICACIDTOTHESERIESWORKINGSTOCKPLASMASOLUTIONSOFCEFATTHECONCENTRATIONSOF10、8、25、075、02、005、002AND001GML1,RESPECTIVELY3ASTOCKSOLUTIONOFIS10MGML1WASPREPAREDINMETHANOLANDDILUTEDWITHMETHANOLCONTAINING1FORMICACIDTOTHEWORKINGSOLUTIONCONTAINING1GML1ISTOA100LPLASMAWASADDED100LOFISWORKINGSOLUTIONAND200LMETHANOLCONTAINING1FORMICACID,THENMIXEDFOR05MINANDTHEMIXTUREWASCENTRIFUGED10000RMIN1FOR10MINTHE100LSUPERNATANTWASTRANSFERREDTOANOTHERTUBEANDDILUTEDWITH400LWATERCONTAINING1FORMICACID,ANDTHENTRANSFERREDINTOAUTOSAMPLERVIALSANDINJECTED10LFORHPLCMS/MSANALYSISALLTHECOURSESOFSAMPLEPREPARATIONWEREKEPTFROMLIGHT14CORROBORATIONOFMETHODSPLASMACALIBRATIONCURVESWASPREPAREDASABOVEMENTIONEDMETHODBYADDING100LOFTHESERIESWORKINGSTOCKPLASMASOLUTIONSTHECALIBRATIONCURVEWASCONSTRUCTEDBYPLOTTINGA1/C2WEIGHTEDLEASTSQUARESLINEARREGRESSIONOFCEFTOTHEISPEAKAREARATIOVERSUSTHESPIKEDCONCENTRATIONOFCEFTHEEXTRACTIONEFFICIENCYOFCEFFROMPLASMAWASDETERMINEDBYANALYZINGTHEQUALITYCONTROLSSAMPLESTHEABSOLUTERECOVERYINTHREECONCENTRATIONS8,075,002GML1WEREDETERMINEDBYCOMPARINGPEAKAREASOBTAINEDFROMPLASMASAMPLEWITHTHOSEFOUNDBYDIRECTINJECTIONOFANSTANDARDSOLUTIONBEINGDILUTEDWITH5ACETICACIDINWATERFROMCEFSTOCKSOLUTIONATTHESAMECONCENTRATIONUSINGTHESAMECONDITIONSTHEMETHODRECOVERYWASDETERMINEDBYCOMPARINGCONCENTRATIONOBTAINEDTHROUGHTHECALIBRATIONCURVEVERSUSTHATHADBEENADDEDTHEINTRADAYANDINTERDAYPRECISIONSWEREASSAYEDBYDETERMININGPLASMASAMPLESWITHTHECONCENTRATIONSOFTHREELEVELSLOW,MEDIUM,HIGHFORSIXTIMESWITHINONEDAYORWITHINFOURCONSECUTIVEDAYSTABLE1RECOVERYANDPRECISIONOFCEFINHUMANPLASMAN24CONCENTRATIONGML1ABSOLUTERECOVERYMETHODRECOVERYWITHINDAYBETWEENDAYRSDRSD002832A23513990A23530371346075796A23512988A23524176206800812A235151026A2351934616215SUBJECTANDDESIGNTWENTYHEALTHYMALEVOLUNTEERSAGED21213YEARS,HEIGHT175004M,WEIGHT66354KGWEREENROLLEDINTHISSTUDYALLSUBJECTSWEREHEALTHYDETERMINEDBYTHEIRMEDICALHISTORY,PHYSICALEXAMINATIONS,ANDROUTINELABORATORYTESTSHEMATOLOGY,BLOODCHEMISTRIESANDURINALYSISTHEYWEREASKEDTOAVOIDALLPRESCRIPTIONFORATLEAST10DBEFORETHESTUDYTHOSEWHOHADAHISTORYOFDRUGORALCOHOLABUSEORALLERGYTOTHECOMPONENTSOFCEF,PENICILLINSANDTHOSEWHOHADCONCOMITANTDRUGTHERAPYWEREEXCLUDEDVOLUNTEERSWEREINFORMEDCOMPREHENSIVELYABOUTTHEAIMOFTHESTUDY,THEDRUGTOBETESTED,ITSACTIVITYANDSIDEEFFECTSANDTHENTHEYWEREASKEDTOSIGNANINFORMEDCONSENTTHESCHEMEWASAPPROVEDBYTHEETHICSCOMMITTEEOFBETHUNEINTERNATIONALPEACEHOSPITALANDTHESTUDYWASPERFORMEDATTHEWARDOFCLINICALTRIALINTHEBETHUNEINTERNATIONALPEACEHOSPITALBASEFORTHECLINICALTRIALOFSTATEFOODDRUGADMINISTRATIONOFCHINA4ATWOWAYCROSSOVERDESIGNWASCARRIEDOUTTHE20VOLUNTEERSWERERANDOMLYDIVIDEDINTOTWOGROUPSEACHSUBJECTRECEIVEDASINGLE250MGORALDOSEOFCEF250MGOFCEFFORSUSPENSIONBEINGMIXEDWITH250MLOFWATERUNIFORMLYFOR30SWITHSPOONEITHERTESTORREFERENCEALLDOSESWEREADMINISTEREDINTHEMORNINGFOLLOWINGA12HFASTWATERINTAKEWASALLOWEDAFTER2HANDLOWFATSTANDARDMEALSWEREPROVIDED4HPOSTDOSETHEVOLUNTEERSWEREPROHIBITEDFROMSMOKING,ALCOHOL,CAFFEINEANDOTHERMEDICINEDURINGTHESTUDYTHEYWEREUNDERMEDICALSUPERVISIONATTHESTUDYSITEBLOODSAMPLES3MLWERECOLLECTEDINHEPARINIZEDTUBESJUSTBEFOREDRUGINGESTIONANDAT10,20,30,45,60,90,120,150,180,210,240,AND300MINAFTERTHEADMINISTRATIONTHEBLOODSAMPLESWEREDEPOSITEDFOR10MINANDCENTRIFUGED3500RMIN1FOR10MINTOGETPLASMATHE1MLPLASMAWASTRANSFERREDTOANOTHERTUBEANDMIXEDWITH50LACETICACID5,ANDTHENTHEMIXTUREWASFROZENAT20BEFOREANALYSISTHECOURSESOFSAMPLECOLLECTINGWEREKEPTFROMLIGHTAFTERA7DAYWASHOUTINTERVALTHETWOGROUPSTOOKTHEOTHERDRUGRESPECTIVELYANDBLOODSAMPLESWERETAKENINTHESAMEWAY16DATAANALYSISANDSTATISTICALMETHODSTHEPLASMACEFLEVELSWERECALCULATEDBYTHECEFCONCENTRATIONSOFTHE20SUBJECTSATDIFFERENTTIMETHECMAXMAXIMUMPLASMACONCENTRATION,THETMAXTIMETOREACHCMAX,WEREOBTAINEDDIRECTLYFROMTHEDATAWITHOUTINTERPOLATIONAFTERTHEADMINISTRATIONTHEAUC05HTHEAREAUNDERCONCENTRATIONTIMECURVEFROM0TO5H,THEAUC0A236THEAREAUNDERCONCENTRATIONTIMECURVEFROMTOINFINITY,ANDTHET1/2ELIMINATIONHALFTIMEWEREAUTOMATICALLYCALCULATEDBYTHEDRUGANDSTATISTICSDASVER10PROGRAMDASWASUSEDTOCARRYOUTTHEANALYSISOFVARIANCEANOVAANDTWOONESIDETTESTSWASEMPLOYED,INORDERTOKNOWNIFTHEMAINPHARMACOKINETICSPARAMETERSBETWEENTWODRUGSOFTHE20SUBJECTSHADSIGNIFICANTDIFFERENCEANDIFTHETABLETSWEREEQUIVALENTTMAXWASANALYZEDWITHWILCOXONSRANKSUMTEST,WHILECMAX,AUC05HANDAUC0A236WERELOGARITHMICALLYTRANSFORMED,EVALUATEDBYVARIANCEANALYSISMETHODTHETWOONESIDETHYPOTHESESATTHE005LEVELOFSIGNIFICANCEWOULDBETREATEDFORCMAX,AUC05H,ANDAUC0A236TOEVALUATETHEIRBIOEQUIVALENTRELATIVEBIOAVAILABILITYWASEXPRESSEDASFOLLOWFAUC05H,T/AUC05H,R1002RESULTS521METHODVALIDATIONUNDERABOVECONDITIONS,CEFANDISWEREWELLSEPARATEDFROMTHEBIOLOGICALBACKGROUND,ANDTHERETENTIONTIMEOFCEFANDISWEREABOUT148MINAND136MIN,RESPECTIVELY,WITHATOTALRUNTIMEOF20MINTHEPEAKSWEREOFGOODSHAPE,ANDNOINTERFERENCEFROMPLASMAMATRIXWASOBSERVEDTHEMRMSCANMODECHROMATOGRAMSOFCEFANDISWERESHOWNINFIG1FIGURE1CHROMATOGRAMSOFCEFANDISBYMULTIPLEREACTIONMONITORINGMRMSCANMODEABLANKPLASMABBLANKPLASMASPIKEDWITHCEFANDISCVOLUNTEERPLASMASAMPLE1CHROMATOGRAMSOFCEF2CHROMATOGRAMSOFISTHEREGRESSIVEEQUATIONWASASFOLLOWSY0764X000105,R09995THELINEARRANGEIS00110GML1,THELIMITOFQUANTITYLOQIS10NGML1THERELATIVESTANDARDDEVIATIONRSDOFINTRADAYANDINTERDAY,ANDTHEABSOLUTEANDMETHODRECOVERIESFORCEFWERESHOWNINTAB1A237A238A239A240A241A242A237A242A238A237A242A238A243A239A244A245A246A247A248A249A250A251A252A253A254A255A1A0A2A13A146FIGURE2MEANPLASMACONCENTRATIONTIMECURVESOFCEFAFTERASINGLEDOSESADMINISTRATIONOFCEFFORSUSPENSIONSIN20HEALTHYVOLUNTEERSTAB2PHARMACOKINETICPARAMETERSOFCEFAFTERASINGLEDOSESOFCEFFORSUSPENSIONSIN20HEALTHYVOLUNTEERSA3A4A5SPARAMETERSTESTREFERENCECMAX/GML1900A6168959A6161TMAX/H037A6012035A6005T1/2/H088A6016087A6011AUC05H/GHML1791A6100791A6110AUCOA7/GHML1798A6102798A6111F1007A612522PHARMACOKINETICPARAMETERSANDBIOEQUIVALENCETHETIMECONCENTRATIONCURVESOFTHETWODRYSUSPENSIONSAFTERSINGLEDOSESADMINISTRATIONWERESHOWNINFIG2THEMAINPHARMACOKINETICPARAMETERSWERESHOWNINTAB2THERESULTSSHOWEDTHATTHEREWASNOTSIGNIFICANTDIFFERENCEP005BETWEENTHETWOTABLETSINCMAX,TMAX,AUC05HANDAUC0A8,SUGGESTINGTHATTHEPLASMADRUGCONCENTRATIONSFLUCTUATIONOFTHETWOSUSPENSIONSWASSIMILARRELATIVEBIOAVAILABILITYOFTHETESTWAS1007125THE90CONFIDENCEINTERVALSOFLNCMAX,LNAUC0A9,LNAUC05HANDLNAUC0A8WERESHOWNINTAB3TAB3THERESULTOFTHETWOONESIDETESTS005PARAMETERST1T290CONFIDENCEINTERVALSLNCMAX11087588749A109993LNAUC05H135113539719A1010292LNAUC0A11133913579732A1010307P005,CRITICALVALUEOFTWOONESIDETESTSIS17323ADVERSEREACTIONDURINGTHESTUDY,THEREWASNOLOCALORSYSTEMICREACTIONSANDSEVEREADVERSEREACTIONOBSERVEDTHERESTSUBJECTSWEREALLINGOODCONDITIONS3DISCUSSIONTHELCMS/MSISAVERYPOWERFULADDITIONTOTHEREPERTOIREOFMETHODSAVAILABLEFORBIOANALYTICALCHEMISTSDEVELOPINGHIGHLYSENSITIVEASSAYSOFBIOFLUIDSNUMEROUSBIOANALYTICALMETHODSHAVEBEENDEVELOPEDINTHEPAST78YEARSUSINGTHISMETHODOFCHOICEFORSUPPORTINGCLINICALANDPRECLINICALPHARMACOKINETICSTUDIESTHECOMMONPERCEPTIONISTHATUTILIZATIONOFLCMS/MSPRACTICALLYGUARANTEESSPECIFICITYSAMPLEPREPARATIONMAYBESIMPLIFIEDOREVENELIMINATED,ANDNOORVERYLITTLECHROMATOGRAPHICSEPARATIONISREQUIREDCHROMATOGRAPHICRUNTIMESAREVERYSHORT,ALLOWINGHIGHTHROUGHPUTDETERMINATIONOFANALYTESINCOMPLEXBIOLOGICALMATRIXESWEREPORTTHEUSEOFASENSITIVELCMS/MSTECHNIQUETOMEASURECEFINHUMANPLASMACOMPAREDWITHOTHERMETHODS,THETECHNIQUEHASTHEADVANTAGESOFINCREASEDSENSITIVITYANDSHORTERRUNTIMESTHESPECIFICITYOFLCMS/MSDETECTIONGREATLYMINIMIZESTHERISKOFINTERFERENCEFROMOTHERSUBSTANCESTHISISESPECIALLYIMPORTANTWHENANALYZINGSPECIMENSFROMPATIENTSSUCHASTHOSEWITHINFECTIONSWHOARETAKINGNUMEROUSCONCOMITANTMEDICATIONS,ANDITCANBEUSEDINTHELOWLIMITDETECTIONFORPHARMACOKINETICSTUDIESANDTHERAPEUTICMONITORINGOFCEF7THETREATMENTOFINFECTIOUSDISEASESININFANTSANDCHILDRENISGREATLYAFFECTEDBYCOMPLIANCEISSUES,ASTHEUNPLEASANTTASTE