二甲双胍-白藜芦醇复合物油包水型纳米乳在体肠吸收及其药代动力学研究

In situ intestinal absorption and pharmacokinetic study of metformin-resveratrol compound water-in-oil nanoemulsion

考察二甲双胍-白藜芦醇复合物油包水型纳米乳(metformin-resveratrol compound water-in-oil nanoemulsion,MRCE)在大鼠体内的在体肠吸收特性和药代动力学行为。通过构建大鼠在体肠单向灌流模型,研究MRCE在不同肠段的吸收情况,大鼠被随机分为两组,二甲双胍和MRCE灌胃给药后,在预设时间点取血,HPLC法测定肠灌流样品和各时间点血样中二甲双胍的含量,绘制血药浓度-时间曲线,DAS 2.1.1软件处理并分析药代动力学数据。MRCE在各肠段的吸收速率常数(K_(a))、有效渗透率(P_(eff))和吸收百分率(PA)均显著高于二甲双胍(P<0.05);MRCE的血药浓度-时间曲线下面积(AUC_(0-72 h))、半衰期(t_(1/2))和平均滞留时间(MRT_(0-72 h))分别为二甲双胍的1.68、11.25和6.97倍(P<0.01)。MRCE的相对生物利用度为167.6%。MRCE的AUC_(0-72 h)的90%可置信区间为156.9%~187.4%,不在生物等效性标准区间内。MRCE肠道吸收情况明显优于游离二甲双胍;结果表明,MRCE提高了二甲双胍的口服生物利用度,且与二甲双胍生物不等效。

To investigate the in situ intestinal absorption characteristics and pharmacokinetic behavior of metfor-min-resveratrol compound water-in-oil nanoemulsion(MRCE)in rats,the in situ intestinal perfusion model wasconstructed in rats to study the intestinal absorption characteristics of MRCE in different intestinal segments.Male Sprague-Dawley rats were randomly divided into two groups.After intragastric administration of metforminand MRCE,blood was taken at a preset time point.The content of metformin in intestinal perfusion samples andblood samples at various time points was determined by HPLC.Plasma concentration-time profiles of free metfor-min and MRCE were calculated,and the main pharmacokinetic data were processed and analyzed by DAS 2.1.1 software.The absorption rate constant(K_(a)),the effective permeability(P_(eff))and the percentage of absorption(PA)of MRCE in each intestinal segment were significantly higher than those of metformin(P<0.05).The areaunder the drug-time curve(AUC_(0-72 h)),the half-life(t_(1/2))and mean residence time(MRT_(0-72 h))of MRCE were 1.68,11.25 and 6.97 times of metformin,respectively(P<0.01).The relative bioavailability of MRCE was 167.6%.The 90%confidence interval of AUC_(0-72 h)was 156.9%-187.4%,which was not within the standard interval of bioequivalence.The intestinal absorption of MRCE was significantly better than that of free metformin;MRCEimproved the oral bioavailability of metformin and was not bioequivalent to metformin.