【摘要】：目的：研究鹽酸西莫替尼對(duì)小腸上皮細(xì)胞跨膜轉(zhuǎn)運(yùn)的影響及機(jī)制,初步探討胃腸道毒性的產(chǎn)生原因,為指導(dǎo)鹽酸西莫替尼臨床合理用藥、開(kāi)發(fā)EGFR-TKIs更為優(yōu)良的劑型提供依據(jù)。 方法：使用大鼠藥動(dòng)學(xué)模型研究鹽酸西莫替尼對(duì)跨膜轉(zhuǎn)運(yùn)的影響；采用大鼠在體小腸灌流以及Caco-2細(xì)胞小室模型研究鹽酸西莫替尼對(duì)小腸被動(dòng)跨膜轉(zhuǎn)運(yùn)的改變；通過(guò)HPLC-UV法測(cè)定藥物的濃度；應(yīng)用Real-time PCR以及Western blots試驗(yàn)檢測(cè)細(xì)胞連接基因表達(dá)水平的變化。藥動(dòng)學(xué)參數(shù)通過(guò)WinNonlin6.1計(jì)算并使用SPSS13.0軟件進(jìn)行統(tǒng)計(jì)分析。 結(jié)果：藥動(dòng)學(xué)研究表明,大鼠多次給予鹽酸西莫替尼后,體重及攝食量均下降,合用PepT1底物藥頭孢克洛、伐昔洛韋和非底物藥阿昔洛韋時(shí),均顯著增加了這些藥物的體內(nèi)暴露量。Caco-2細(xì)胞小室模型以及大鼠在體小腸灌流試驗(yàn)均顯示鹽酸西莫替尼能增加細(xì)胞旁路轉(zhuǎn)運(yùn)標(biāo)志物熒光素鈉的透過(guò)率,而不增加被動(dòng)跨細(xì)胞轉(zhuǎn)運(yùn)標(biāo)志物普萘洛爾的透過(guò)率。Real-time PCR以及Western Blots試驗(yàn)顯示,鹽酸西莫替尼處理后的Caco-2細(xì)胞以及大鼠小腸細(xì)胞連接基因中Afadin基因的nRNA及蛋白表達(dá)量顯著降低。 結(jié)論：鹽酸西莫替尼通過(guò)顯著降低細(xì)胞連接基因中Afadin基因的表達(dá),增加小腸上皮細(xì)胞的旁路轉(zhuǎn)運(yùn)而非被動(dòng)跨細(xì)胞轉(zhuǎn)運(yùn),從而增加小腸的非特異性吸收,增加合用藥物的暴露量。因此在臨床上,鹽酸西莫替尼與其它藥物合用過(guò)程中,應(yīng)調(diào)整給藥劑量以避免藥物相互作用的風(fēng)險(xiǎn)。
[Abstract]:Objective: to study the effect and mechanism of Simotinib Hydrochloride on transmembrane transport of small intestinal epithelial cells, and to explore the causes of gastrointestinal toxicity, so as to provide evidence for guiding the rational use of Simotinib Hydrochloride and developing a better dosage form of EGFR-TKIs. Methods: the effects of Simotinib Hydrochloride on transmembrane transport were studied by pharmacokinetics model in rats, and the effects of Simotinib Hydrochloride on passive transmembrane transport of small intestine were studied by in vivo small intestinal perfusion and Caco-2 cell chamber model. HPLC-UV assay was used to determine the concentration of drugs, and Real-time PCR and Western blots tests were used to detect the changes of cell junction gene expression. The pharmacokinetics parameters were calculated by WinNonlin6.1 and statistically analyzed by SPSS13.0 software. Results: the pharmacokinetics study showed that the body weight and food intake decreased after repeated administration of Simotinib Hydrochloride in rats. When combined with cefaclor, valaciclovir and acyclovir, the substrate drugs of PepT1, cefaclor, valaciclovir and acyclovir were used in combination with cefaclor, valaciclovir and acyclovir. The in vivo exposure of these drugs was significantly increased. CaCO3-2 cell chamber model and rat intestinal perfusion test in vivo showed that simotidine hydrochloric acid could increase the transmittance of fluorescein sodium, a marker of cell bypass transport. Without increasing the transmittance of propranolol, a passive transcellular transport marker. Real-time PCR and Western Blots tests showed that The expression of Afadin gene nRNA and protein in Caco-2 cells and rat small intestine cells treated with Simotinib Hydrochloride decreased significantly. Conclusion: Simotinib Hydrochloride can increase the nonspecific absorption of small intestine and increase the exposure of combined drugs by significantly reducing the expression of Afadin gene in cell junction gene and increasing the bypass transport rather than passive transcellular transport of small intestinal epithelial cells. Therefore, in the clinical process of combination of Simotinib Hydrochloride and other drugs, the dose of Simotinib Hydrochloride should be adjusted to avoid the risk of drug interaction.
【學(xué)位授予單位】：中南大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2014
【分類(lèi)號(hào)】：R96

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