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1、Pharmacokineticsandbio-PharmacokineticsofglucosidasePALAbstractObjective:ThepharmacokineticsofglucosidasePALwasStudiedindogs.TheabsorptionkineticsandSiteofglucosidasePALwereexploredinthegastrointestinalinrats.ThefurtherobjectivewastopredicttheProcessofglucosidasePALinhumanexactlyandprovidet
2、hescientificbasistodeterminethedruginclinicaldrugforms.Methods:TheuseofLC-MSstudythePharmacokineticsoftheglucosidasePALinBeagle;Theabsorptionkineticsandabsorptionsitewereinvestigatedinratsusingintestineperfusionmethod.Results:GlucosidasePAL’bulkdrugsandcapsulewereadministeredtodogsatasingle
3、didof5and8mg/kg,5mg/kgbyinjection.respectively,t1/2ka=24.9min,AUC(ug·min)/mL=54.35;t1/2ka=25.3min,AUC(ug·min)/mL=106.4;t1/2α=4.22min,AUC(ug·min)/mL=133.1.Afterdrugbytheoral,intravenousadministration,thedruginvivoBeagle’sabsolutebioavailabilityof40.74%and49.96%.Theabsorptionpercentageinoneho
4、ur(P%)atintestinewas26.68%,andthehourlyabsorptionpercentagesofglucosidasePALinduodenum,Jejunum,colonandileumwere37.97%，36.10%，25.02%,11.23%,-1-1respectively,differentdrugconcentrations:0.80mg·ml,0.40mg·ml,-10.16mg·ml,theabsorptionpercentageinonehouratintestinewere26.68%,26.12%,25.65%.Conclu
5、sion:GlucosidasePALismoderatelyabsorbedinstomach,buthasnospecificabsorptionsiteintheintestine,itprovidesthescientificbasisto2determinethedruginclinicaldrugforms.Keywords:glucosidasePAL;pharmacokinetic;liquidchromatography-tandemmassspectrometry;Gastrointestinalabsorption3引言糖苷PAL進(jìn)入體內(nèi)后，前期實(shí)驗(yàn)表明
6、會(huì)在很短的時(shí)間代謝成葡磷酰胺(glufosfamide)，從而發(fā)揮藥效，其在臨床研究上屬于前體藥物。葡磷酰胺的化學(xué)名為β-D-吡喃葡萄糖基-N,N’-二(2-氯乙基)磷酰胺，英文名為β-D-GlucopyranosyI-[N,N'-bis[(2-chloroethyl)]phosphoricaciddiamide，為一種新型的烷化劑類抗腫瘤藥物，是由一分子具有直接烷化作用的異磷酰胺氮芥與一分子葡萄糖通過糖苷鍵相連而形成的。葡磷酰胺在鈉依賴性的葡萄糖跨膜轉(zhuǎn)運(yùn)蛋白SAAT1的作用下轉(zhuǎn)運(yùn)進(jìn)入腫瘤細(xì)胞，然后通過水解釋放異磷酰胺氮芥而發(fā)揮活性，具有抗乳腺癌、結(jié)腸癌、非小細(xì)胞肺癌和胰腺癌
7、的活性。目前在國(guó)內(nèi)對(duì)糖苷PAL研究正處于臨床前開發(fā)階段，為了更準(zhǔn)確地預(yù)測(cè)糖苷PAL在人體內(nèi)的藥動(dòng)學(xué)行為，本文將采用液-質(zhì)聯(lián)用技術(shù)和在體腸灌流模型分別對(duì)糖苷PAL在比格犬體內(nèi)的藥動(dòng)學(xué)和大鼠體內(nèi)的胃腸吸收動(dòng)力學(xué)進(jìn)行詳細(xì)地研究。本實(shí)驗(yàn)擬研究以下內(nèi)容：1．建立測(cè)定生物樣品中糖苷PAL的定量分析方法2．考察糖苷PAL的血漿蛋白結(jié)合率3．初步闡明糖苷PAL在動(dòng)物體內(nèi)的藥動(dòng)學(xué)行為4．初步闡明糖苷PAL的絕對(duì)生物利用度5．建立合適的模型，考察糖苷PAL在大鼠體內(nèi)的吸收情況通過對(duì)糖苷PAL的藥動(dòng)學(xué)和生物藥劑學(xué)的研究，初步
