结肠靶向护肠清毒微丸中大黄素在大鼠体内肠吸收及药物动力学研究

孙萍等

摘要：目的 建立護肠清毒微丸灌胃后大鼠血浆和结肠组织中大黄素浓度高效液相色谱测定方法，探讨试验微丸在大鼠体内药物动力学性质及结肠组织分布情况。方法 将Wistar大鼠随机分为微丸组和普通胶囊组，分别予护肠清毒微丸和胶囊内容物灌胃后，于给定的时间点（1、2、3、4、5、6、8、12、24 h）从大鼠静脉窦取血分析。处死大鼠，分离结肠组织，进行提取分析。色谱条件：Phenomenex C18柱（4.6 mm×150 mm，10 ?m），流动相为甲醇-0.1%冰醋酸溶液（80∶20），流速1 mL/min，检测波长254 nm。结果 大黄素在0.102～20.40 ?g/mL范围内线性关系良好。回归方程分别为：血浆溶液A=76 825C+3567.8，r=0.999 4（n=6）；结肠组织溶液A=75931C+3384.2，r=0.999 0（n=6）。日间精密度和日内精密度均<4.0%，提取回收率>90.0%。微丸组大鼠血液和结肠组织中所含大黄素的药物动力学参数T1/2和Tmax较普通胶囊组有所延长，Cmax和AUC0-24较普通胶囊组明显提高。结论 护肠清毒微丸具有控释和结肠靶向的作用。

关键词：护肠清毒微丸；大黄素；结肠靶向；药物动力学

DOI：10.3969/j.issn.1005-5304.2015.09.022

中图分类号：R285 文献标识码：A 文章编号：1005-5304（2015）09-0079-04

Pharmacokinetic and Intestinal Absorption Study on Rats of Emodin in Colon-Targeted Huchang Qingdu Pellets SUN Ping1， MA Chuan-jiang1， LIU Le-yang2 （1.Affiliated Hospital of Shandong University of Traditional Chinese Medicine， Jinan 250011， China；2.Shandong University of Traditional Chinese Medicine， Jinan 250000， China）

Abstract：Objective To establish an HPLC method for concentration determination of emodin in plasma and colon tissues after gavage with Huchang Qingdu Pellets；To explore pharmacokinetic properties and colon tissue distribution of Huchang Qingdu Pellets in rats. Methods Wistar rats were randomly divided into Pellets group and ordinary capsule group. Blood was taken after gavage with Huchang Qingdu Pellets or capsule content in given time points （1， 2， 3， 4， 5， 6， 8， 12， 24 h） from rat venous sinus and analyzed. Rats were put to death， and gastric and colon tissues were isolated and extracted for analysis. Chromatographic conditions：Phenomenex C18 column （4.6 mm × 150 mm， 10 μm）， the mobile phase of methanol-0.1% acetic acid solution （80∶20）， flow rate of 1 mL/min， the detection wavelength of 254 nm. Results Emodin was in good linear range of 0.102-20.40 μg/mL. The regression equations were：plasma solution A=76 825C + 3567.8， r=0.999 4 （n=6）；intestinal tissue solution A=75 931C + 3384.2， r=0.999 0 （n=6）. Day-to-day precision and within-day precision were less than 4%. The recovery rate was more than 90%. Pharmacokinetic parameters of T1/2 and Tmax of emodin in rat blood and intestinal tissues increased compared with the ordinary capsule group；Cmax and AUC0-24 were obviously improved compared with the ordinary capsule group. Conclusion Huchang Qingdu Pellets do have controlled release and colon targeting effect.

Key words：Huchang Qingdu Pellets；emodin；colon targeting；pharmacokinetics

结肠靶向护肠清毒微丸为山东中医药大学附属医院院内制剂，具有健脾清肠、化瘀解毒功效。处方由大黄、赤芍、紫草等10味中药组成，临床对肝病和肠源性内毒素血症的治疗有明显疗效[1-3]。结肠靶向护肠清毒微丸是对处方药物进行提取精制后，加入果胶钙制备微丸丸芯，经聚丙烯酸树脂包衣，制备成结肠定位靶向给药的控释微丸。

大黄为方中君药，具有泻热通肠、凉血解毒、逐瘀通经功效。大黄素为大黄的主要有效成分，有研究表明其对缺血再灌注损伤具有保护作用[4-5]。本试验选择大黄的主要有效成分大黄素为考察指标，比较结肠靶向护肠清毒微丸和普通胶囊内容物经大鼠口服后大黄素在血液及结肠组织中药物动力学性质，为进一步探讨护肠清毒微丸的作用机制和药效学评价提供试验依据。……