CAJ | 학술논문

目的合成菌群触发型结肠靶向吲哚美辛前药,评价其体内外释药特性与抑制结肠癌肝转移的效应.方法合成吲哚美辛.直链淀粉酯(IDM-Ams),通过傅里叶变换红外光谱(FTIR)和核磁共振波谱(NMR)观察其结构表征.通过体外胃肠道模拟,筛选出具有结肠靶向潜能的前药IDM-AM-3.比较原药组、前药组和对照组大鼠灌胃后不同时点外周血和门静脉血的药物浓度和药代动力学特点.建立裸鼠结肠癌肝转移模型,观察IDM-AM-3对裸鼠结肠癌肝转移的抑制效果.结果共合成6种不同载药量的IDM-Ams,其中IDM-AM-3在模拟胃液(4h)、小肠环境(6h)和结肠环境(36h)中的释放率分别为1.3%、9.3%和95.3%.药代动力学检测结果显示,IDM-AM-3较IDM吸收明显滞后,门静脉血达峰时间[T_(max),(11.35±2.45)h]、平均滞留时间[MRT,(22.27±0.52)h]和t_(1/2)[(16.74±4.04)h]显著延长,峰血药浓度[C_(max),(9.69±2.40)mg/L]和药时曲线下面积[AUC_(0-t),(236.7±13.1)mg·L~(-1)·h]明显降低,外周血AUC_(0-t)[(142.8±5.9)mg·L~(-1)·h]较门静脉血低(均P<0.01).抑瘤实验结果显示,与IDM比较,IDM-AM-3能显著降低结肠癌裸鼠肝转移瘤数目(P<0.05).结论结肠靶向IDM.AM-3具有门静脉缓释特点,为结肠靶向释药系统应用于门静脉缓释治疗提供了部分实验依据.
목적 합성균군촉발형결장파향신타미신전약,평개기체내외석약특성여억제결장암간전이적효응.방법 합성신타미신.직련정분지(IDM-Ams),통과부리협변환홍외광보(FTIR)화핵자공진파보(NMR)관찰기결구표정.통과체외위장도모의,사선출구유결장파향잠능적전약IDM-AM-3.비교원약조、전약조화대조조대서관위후불동시점외주혈화문정맥혈적약물농도화약대동역학특점.건립라서결장암간전이모형,관찰IDM-AM-3대라서결장암간전이적억제효과.결과 공합성6충불동재약량적IDM-Ams,기중IDM-AM-3재모의위액(4h)、소장배경(6h)화결장배경(36h)중적석방솔분별위1.3%、9.3%화95.3%.약대동역학검측결과현시,IDM-AM-3교IDM흡수명현체후,문정맥혈체봉시간[T_(max),(11.35±2.45)h]、평균체류시간[MRT,(22.27±0.52)h]화t_(1/2)[(16.74±4.04)h]현저연장,봉혈약농도[C_(max),(9.69±2.40)mg/L]화약시곡선하면적[AUC_(0-t),(236.7±13.1)mg·L~(-1)·h]명현강저,외주혈AUC_(0-t)[(142.8±5.9)mg·L~(-1)·h]교문정맥혈저(균P<0.01).억류실험결과현시,여IDM비교,IDM-AM-3능현저강저결장암라서간전이류수목(P<0.05).결론 결장파향IDM.AM-3구유문정맥완석특점,위결장파향석약계통응용우문정맥완석치료제공료부분실험의거.
Objective To develope a colon-specific prodrug of Indomethacin microbially triggered,carry out in vitro/in vivo evaluation of drug release.and appraise its inhibitory effect on liver metastasis from colon cancer.Methods Indomethacin prodrugs were synthesized and characterized by FTIR and NMR,and dissolution test simulating gastrointestinal tract was employed to screen the colon-specific prodrug.Then,the pharmacokinetic profile of portal vein and peripheral blood in Sprague-Dawley rats was studied.Lastly,the inhibitory effect on liver metastasis from colon cancer in nude mice was observed.Results The chemical structure characterized by FTIR and NMR demonstrated that six kinds of indomethacin-block-amylose with different drug loading(IDM.AM.1-6)were synthesized,among which IDM-AM-3 was degraded 1.3%,9.3%and 95.3%.respectively,in simulated gastric fluid for 4h,small intestine for 6 h,and colon for 36 h.The pharmacokinetic test of IDM.AM-3 showed that absorption was delayed significantly(P<0.01),peaktime[(11.35±2.45)h],elimination half-life[(16.74±4.04)h]and mean residence time[(22.27±O.52)h]were significantly prolonged(P<0.01),as well as peakserum concentrations[(9.69±2.40)mg/L]and AUC_(0-t)[(236.7±13.1)mg·L~(-1)·h]were decreased markedly(P<0.01) as compared with those of IDM regarding to portal vein.Additionally,its AUC_(0-t)in peripheral blood was remarkably lower than that in Portal vein(P<0.01).The tumor suppression observation showed that it could remarkably reduce the number of liver metastases in contrast to IDM(P<0.05).Conclusionpossesses advantage of sustained release in portal vein providing some experimental basis for colon-specific delivery system applied to sustained release in the portal vein.