盐酸西莫替尼对小肠上皮细胞跨膜转运影响研究
发布时间：2019-05-17 21:32
【摘要】：目的：研究盐酸西莫替尼对小肠上皮细胞跨膜转运的影响及机制,初步探讨胃肠道毒性的产生原因,为指导盐酸西莫替尼临床合理用药、开发EGFR-TKIs更为优良的剂型提供依据。 方法：使用大鼠药动学模型研究盐酸西莫替尼对跨膜转运的影响；采用大鼠在体小肠灌流以及Caco-2细胞小室模型研究盐酸西莫替尼对小肠被动跨膜转运的改变；通过HPLC-UV法测定药物的浓度；应用Real-time PCR以及Western blots试验检测细胞连接基因表达水平的变化。药动学参数通过WinNonlin6.1计算并使用SPSS13.0软件进行统计分析。 结果：药动学研究表明,大鼠多次给予盐酸西莫替尼后,体重及摄食量均下降,合用PepT1底物药头孢克洛、伐昔洛韦和非底物药阿昔洛韦时,均显著增加了这些药物的体内暴露量。Caco-2细胞小室模型以及大鼠在体小肠灌流试验均显示盐酸西莫替尼能增加细胞旁路转运标志物荧光素钠的透过率,而不增加被动跨细胞转运标志物普萘洛尔的透过率。Real-time PCR以及Western Blots试验显示,盐酸西莫替尼处理后的Caco-2细胞以及大鼠小肠细胞连接基因中Afadin基因的nRNA及蛋白表达量显著降低。 结论：盐酸西莫替尼通过显著降低细胞连接基因中Afadin基因的表达,增加小肠上皮细胞的旁路转运而非被动跨细胞转运,从而增加小肠的非特异性吸收,增加合用药物的暴露量。因此在临床上,盐酸西莫替尼与其它药物合用过程中,应调整给药剂量以避免药物相互作用的风险。
[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.
【学位授予单位】：中南大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R96
[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.
【学位授予单位】：中南大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R96
【参考文献】
相关期刊论文 前4条
1 龚倩;胡哲益;黄志壮;王黎青;刘文芳;郭歆;曹伟;王霆;程泽能;;头孢克洛与溴己新在中国健康人体内药动学环节的相互作用(英文)[J];中南大学学报(医学版);2007年05期
2 黄继汉,黄晓晖,陈志扬,郑青山,孙瑞元;药理试验中动物间和动物与人体间的等效剂量换算[J];中国临床药理学与治疗学;2004年09期
3 赵e，
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