本文選題：抗體偶聯(lián)細(xì)胞毒素制劑藥物(ADC) + T-DM1　； 參考：《復(fù)旦大學(xué)》2014年碩士論文

【摘要】：曲妥珠單抗-美登木素生物堿(T-DM1)是一類抗體偶聯(lián)細(xì)胞毒素制劑藥物(Antibody Drug Conjugates ADC),其臨床用于人表皮生長因受體-2(HER2)陽性乳腺癌治療。本文針對(duì)它的兩種代謝產(chǎn)物DM1-MC C與DM1,綜合藥代動(dòng)力學(xué)的研究方法和檢測手段,通過藥物的吸收、分布、代謝、排泄特性(ADME)和藥動(dòng)學(xué)參數(shù)等方面闡述了它們的藥代動(dòng)力學(xué)概況。論文的第一章,綜述了HER2陽性乳腺癌治療藥物T-DM1臨床前和臨床研究概況�；仡櫫怂幋鷦�(dòng)力學(xué)與類藥性質(zhì)概念并深入討論藥物在發(fā)現(xiàn)階段的研究思路。此外,巰基化合物在藥物遞送系統(tǒng)(DDS)有廣泛應(yīng)用,它具有腫瘤細(xì)胞的靶向性質(zhì)在藥物設(shè)計(jì)與開發(fā)中得到很大重視。本章基于DM1與DM1-MCC結(jié)構(gòu)特征,討論并分析了其研究現(xiàn)狀與代謝方式為后文中藥動(dòng)學(xué)實(shí)驗(yàn)方案提供理論依據(jù)與參考。在第二章為實(shí)驗(yàn)部分,分為(1)分別選擇4個(gè)種屬Balb/c裸鼠、SD大鼠、比格犬與人的血漿考察DM1-MCC與游離DM1血漿穩(wěn)定性數(shù)據(jù)；(2)使用MDR1-MDCK細(xì)胞株單層膜通透模型研究DM1-MCC滲透性；(3)以多種給藥途徑靜脈注射、腹腔注射、經(jīng)口灌胃(10% captisol制劑)、經(jīng)口灌胃(玉米油制劑)給藥Balb/c裸鼠；靜脈注射、皮下注射(SC)、口服給藥比格犬DM1-MCC,采用液質(zhì)聯(lián)用技術(shù)(LC-MS/MS)同時(shí)測定DM1-MCC、游離態(tài)DM1與總DM1血藥濃度。得到的結(jié)果為：(1)血漿穩(wěn)定性實(shí)驗(yàn)顯示DM1-MCC于Balb/c裸鼠、SD大鼠血漿半衰期極短分別為t1/2lmin和t1/2=1.5min,而比格犬與人血漿中相對(duì)穩(wěn)定。游離DMl于Balb/c裸鼠、SD大鼠與人血漿有相近清除行為,半衰期分別為t1/2= 13.2min、11.7min和29min；比格犬t1/2=108.5min。(2)MDR1-MDCK單層膜通透性數(shù)據(jù)表明DM1-MCC有低滲透性與高外排率,各濃度下RE均大于15。(3)Balb/c裸鼠藥動(dòng)學(xué)參數(shù)顯示DM1-MCC有極快的清除率,在所有給藥途徑中均未測得(LLOQ=1ng/m11。游離DM1在IP給藥途徑下Tmax=0.25hr, Cmax=24.4ng/ml, t1/2=2hr, AUCiast=18.1 hr·ng/ml�？侱M1在1V給藥后Cl=16.5L/hr/kg, Vss=11.2L/kg, MRTINF=0.681hr; IP、PO(10% captisol制劑)、PO(玉米油制劑)給藥后生物利用度(F)分別為133%、5.43%和19.8%。DM1-MCC分別在比格犬＝和SC中觀察到,而更高濃度的游離DMl和總DM1在各給藥方式下測得。其中,IV途徑游離DM1與總DM1參數(shù)分別是Cl=1.05L/hr/kg和0.436L/hr/kg, Vss=0.466和1.35, t1/2=0.576hr和5.67hr, AUCiast=104.2hr·ng/ml和213hr·ng/ml, MRTINF=0.531hr和2.77hr。比格犬SC、PO給藥后生物利用度分別為89.1%和45.8%。第三章中我們對(duì)研究工作進(jìn)行匯總并得到結(jié)論。含硫酯的DM1-MCC在血漿中容易水解,導(dǎo)致Balb/c裸鼠與比格犬血藥濃度維持在較低水平。由DM1-MCC高外排率推測其可能是p-gp泵出底物,此外低溶解度導(dǎo)致其滲透性差。DM1-MCC玉米油制劑相對(duì)于10% captisol能夠顯著提高DMl在Balb/c裸鼠體內(nèi)的生物利用度。比格犬游離DM1血藥濃度普遍高于Balb/c裸鼠表明其可能有更大毒性風(fēng)險(xiǎn)。
[Abstract]:Tratozumab-Madden lignin alkaloid (T-DM1) is a class of Antibody drug conjugate ADCs, which is used in the treatment of human epidermal growth factor receptor 2 (HER2) positive breast cancer. In this paper, the pharmacokinetics of DM1-MC C and DM1, two metabolites of DM1-MC C and DM1, were reviewed in terms of their absorption, distribution, metabolism, excretion characteristics (ADME) and pharmacokinetic parameters. In the first chapter, the preclinical and clinical studies of Her2-positive breast cancer drug T-DM1 are reviewed. The concepts of pharmacokinetics and pharmacokinetic properties were reviewed. In addition, sulfhydryl compounds are widely used in drug delivery system (DDS). Based on the structural characteristics of DM1 and DM1-MCC, this chapter discusses and analyzes the present research status and metabolic patterns of DM1 and DM1-MCC, which provide theoretical basis and reference for the later experimental scheme of Chinese traditional medicine. In the second chapter, the experiment was divided into (1) the plasma stability data of DM1-MCC and free DM1 were investigated in the plasma of four Balb / c nude mice SD rats, Beagle dogs and human plasma, (2) the permeability of DM1-MCC was studied by using MDR1-MDCK cell line monolayer membrane permeability model. (3) Balb / c nude mice were given intravenously, intraperitoneally, orally (10% captisol), and orally (corn oil) by various ways. The plasma concentrations of free DM1 and total DM1 were determined by LC-MS / MS method after subcutaneous injection (SC) and oral administration of DM1-MCC. The results were as follows: (1) the plasma stability test showed that the plasma half-life of DM1-MCC in Balb / c SD rats was very short (t1/2lmin and t 1 / 2) 1.5 mins, and that in Beagle dogs and human plasma was relatively stable. Free DMl in Balb / c nude rat / SD rats was similar to that in human plasma, and the half-life was t _ 1 / 2 = 13.2min ~ 11.7min and 29min, respectively, while in Beagle dog t _ 1 / 2108.5min. (2) the permeability data of MDR1-MDCK monolayer membrane showed that DM1-MCC had low permeability and high efflux rate. (3) the pharmacokinetic parameters of Balb / c nude mice showed that DM1-MCC had an extremely fast clearance rate, which was not detected in all drug delivery pathways (LLOQN 1ng / m11). Free DM1 was treated by IP administration with Tmaxl 0.25hr-1, Cmaxl 24.4ng / ml, T1 / 2ng / ml, AUCiasta 18.1 hr / ng.ml. The bioavailability (F) of total DM1 was 1330.43% and 19.8.DM1-MCC were observed in Beagle dog = and SC, respectively, and the higher concentrations of free DMl and total DM1 were observed in Beagle dog = and SC, respectively. The bioavailability of IPPO (10% captisol preparation) and corn oil preparation (F) was 1.33% and 19.8.DM1-MCC, respectively, in Beagle dog = and SC, while the higher concentration of free DMl and total DM1 were measured under different administration modes. The parameters of free DM1 and total DM1 in IV pathway were ClN 1.05L / hr / kg and 0.436L / hr / kg, VSS 0.466 and 1.35, t1/2=0.576hr and 5.67hrl, AUCiast104.2hr ng/ml and 213hr ng / ml, MRTINF0.531hr and 2.77hr. respectively. The bioavailability was 89. 1% and 45. 8%, respectively. In the third chapter, we summarize the research work and draw a conclusion. DM1-MCC containing sulfur ester was easily hydrolyzed in plasma, which resulted in the low concentration of Balb / c in nude mice and Beagle dogs. The high efflux rate of DM1-MCC suggested that DM1-MCC might be the substrate of p-gp pump. In addition, the low solubility of DM1-MCC cornoil preparation could significantly increase the bioavailability of DML in Balb / c nude mice compared with 10% captisol. The plasma concentration of free DM1 in Beagle dogs was generally higher than that in Balb / c nude mice.
【學(xué)位授予單位】：復(fù)旦大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2014
【分類號(hào)】：R965

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