新疆石榴皮多酚抗肿瘤有效部位及其主成分安石榴苷的胃肠道吸收和代谢特性研究

Pomegranate peel is the dry peel of Punica granatum L., which belongs to Punical plant in Punicaceae. It was collected in the Chinese Pharmacopoeia（2010 version）and used to treat chronic diarrhea, chronic dysentery, bloody diarrhea, prolapse of anus, uterine bleeding, abnormal vaginal discharge, abdominal pain parasitic. The polyphenolic compounds of pomegranate peel and its major components punicalagin have good antioxidant, antimicrobial and antitumor activity. The gastrointestinal absorption of punicalagin is low following oral administration. At present, the gastrointestinal absorption and metabolic characteristics of the anti-tumor effective fraction of polyphenol and punicalagin from the pomegranate peel by oral administration are still unclear. .Based on previous research results, the project will separate polyphenols extract and punicalagins, which have antitumor activity, from the peel of Punica granatum L. in xinjiang. The gastrointestinal absorption processes of them were systematically investigated based on the models of intestine loop, Caco-2 cell and whole animal. The metabolic processes of them were systematically investigated based on the intestinal flora metabolic model and rat liver microsomes metabolic model in vitro. It will provide pharmacokinetic basis for the scientific evaluation of the medicinal value of anti-tumor activity of the polyphenol extract from pomegranate peel by oral administration and determine antitumor component in vivo. It will also provide experimental basis for increasing the oral bioavailability and clinical effect when anti-tumor new drug was design in the future.

石榴皮为石榴科石榴属植物石榴 Punica granatum L.的干燥果皮，收载于2010版《中国药典》，用于治疗久泻，久痢，便血，脱肛，崩漏，带下，虫积腹痛。石榴皮中多酚及其主成分安石榴苷具有显著的抗氧化、抗菌及抗肿瘤活性，但安石榴苷口服吸收差，目前，对石榴皮多酚抗肿瘤有效部位及其主成分安石榴苷口服给药后，其在胃肠道的吸收和代谢特性尚不清楚。.在前期工作基础上，本课题以新疆酸石榴皮中提取分离的抗肿瘤多酚精制物及其主成分安石榴苷为研究对象，分别采用大鼠肠襻模型、Caco-2细胞模型、整体实验动物、肠道菌群体外代谢模型和肝微粒体代谢模型研究其在胃肠道的体内外吸收过程和体外代谢过程，为科学评价石榴皮多酚抗肿瘤有效部位口服给药的药用价值和体内抗肿瘤有效成分的确证提供药动学依据，在设计口服抗肿瘤新制剂时为提高生物利用度和临床疗效提供实验依据。

采用大鼠体外、体内和细胞模型系统研究了新疆石榴皮多酚抗肿瘤有效部位主要成分的胃肠道吸收和代谢特性，为评价口服给药的药用价值和药效成分确证提供了药动学依据。. 安石榴苷在大鼠外翻肠囊各肠段的吸收无差异（P>0.05）；低浓度时，吸收速率常数（Ka）回肠>结肠>空肠>十二指肠，高浓度时，空肠>结肠>回肠>十二指肠。.在体灌流模型中的胃肠吸收动力学表明，安石榴苷、鞣花酸在胃部吸收差，在各肠段的Ka和表观渗透系数（Papp）无差异（P>0.05），肠道内无特殊“吸收窗”。安石榴苷为被动扩散；鞣花酸为主动转运，且精制物中其他成分可促进鞣花酸吸收。.鞣花酸在Caco-2细胞模型的摄取和转运量与时间、浓度、pH值、温度、P-gp抑制剂密切相关，并与时间、浓度呈正相关，且吸收强于外排，外排比<1.5，表明以主动转运为主，外排蛋白未参与转运过程，推断其为难吸收药物，溶出是吸收的限速因素；安石榴苷摄取和累计转运量呈时间、浓度、pH值和温度依赖性，与浓度为一级速率特征，P-gp参与了摄取、转运过程，P-gp抑制剂能明显促进其转运，RB-A/A-B＜1.5，双向转运无方向性，主要为被动转运。.大鼠灌服鞣花酸后，分布快，达峰时间短，呈二室模型分布，绝对生物利用度（F）为24.49%，表明胃肠道吸收较差。.采用UPLC-MS/MS法检测、推证代谢途径及代谢产物，大部分安石榴苷经大鼠肠道菌群代谢为M1-1、M1-2、M2、M3和鞣花酸，在大鼠体外肝微粒代谢为鞣花酸和5个代谢物（M1，M2、M3、M4、M5）；体外代谢中有鞣花酸与葡萄糖醛酸结合的代谢物，具UDPGA依赖性。安石榴苷和鞣花酸的大鼠体内代谢研究表明，血浆、尿液、粪便、胆汁等生物样品中均未检测到相关代谢产物。.以上吸收和代谢特性研究结果相互之间得到了印证与支持，安石榴苷、鞣花酸的胃肠道吸收特性和代谢途径研究结果，为剂型设计和提高生物利用度提供了药动学依据。