大豆异黄酮对盐酸雷洛昔芬在大鼠体内的药动学研究

Pharmacokinetics study on compound raloxifene/soybean isoflavone tablet after oral administration in rats

目的:研究大豆异黄酮对盐酸雷洛昔芬在大鼠体内的药动学,并观察大豆异黄酮对盐酸雷洛昔芬药动学参数以及相对生物利用度Frel参数的影响。方法:取SD雌性大鼠8只(390±10)g,随机平均分为两组,对照组为盐酸雷洛昔芬片(RH)组,实验组为大豆异黄酮盐酸雷洛昔芬片(RH-SIF)组,按剂量10.7 mg/kg灌胃给药,分别于0.5、0.75、1、2、4、6、8、12、24、48、72、96、144、192 h取血,处理样品后,以RH为对照品,采用HPLC法测定两组血浆样品中的药物浓度并拟合药时曲线,得出药物动力学参数。采用AIC判别法确定两组制剂在大鼠体内的血药分布所符合的房室模型,并通过AUCT.DR/(AUCR.DT)计算得到RH-SIF片相对生物利用度Frel。结果:①以盐酸雷洛昔芬(RH)为检测指标,给药后两组大鼠体内的主要药动学参数分别为:实验组:Ka为(0.67±0.22)/h,Ke为(0.01±0.00)/h,Tmax为(2.13±0.12)h,Cmax为(0.78±0.02)μg/ml,AUC为(74.64±8.62)μg.h/ml;对照组:Ka为(0.27±0.02)/h,Ke为(0.01±0.00)/h,Tmax为(4.36±1.05)h,Cmax为(0.48±0.13)μg/ml,AUC为(62.73±5.53)μg.h/ml。②与市售的RH片相比,大鼠服用RH-SIF片后,达峰时间明显缩短,达峰浓度明显升高(P<0.05),且两制剂的药时曲线下面积AUC有显著差异(P<0.01)。③相对生物利用度Frel,ie:AUCT.DR/(AUCR.DT)=165.68%。结论:两组制剂在大鼠体内均符合权重为1/C2的单室模型分布,且大豆异黄酮盐酸雷洛昔芬片能明显提高雷洛昔芬的相对生物利用度。

Objective：To provide experimental evidence for absorption mechanism of raloxifence hydrochloride（RH）,pharmacokinetics of compound raloxifence hydrochloride（Co RH） in rats were investigated as well as relative bioavailability（Frel） using RH available on the market as reference preparation.Method： 8 adult female SD rats（390±10 g） were randomly divided into two groups of the RH tablets control group and the Co.RH tablets group.The blood samples were collected at 0.5、0.75、1、2、4、6、8、12、24、48、72、96、144、192 min after oral administration at the dose of 0.7 mg/kg,respectively.Take RH as the reference substance after processing samples.Determine the drug concentration of the two plasma samples by HPLC method and fit the medicine-time curve to conclude the parameters of pharmacodynamics.AIC discriminant method was employed to determine the compartment model,and AUCT·DR/（AUCR·DT） was used to calculate the relative bioavailability（Frel） of compound formulations.Results： ①The pharmacokinetics parameters of both group after oral administration were as follows：The compound raloxifence hydrochloride tablets experimental group： Ka was（0.67±0.22） /h,Ke was（0.01±0.00） /h,Tmax was（2.13±0.12） h,Cmax was（0.78±0.02） μg/ml,AUC was（74.64±8.62） μg·h/ml;the Raloxifence Hydrochloride Tablets control group：Ka was（0.27±0.02） /h,Ke was（0.01±0.00） /h,Tmax was（4.36±1.05） h,Cmax was（0.48±0.13） μg/ml,AUC was（62.73±5.53） μg·h/ml.②Compared with raloxifence hydrochloride tablets available on the market,after oral administration of compound raloxifence Hydrochloride Tablets to rats,Tmax was shorted significantly,and Cmax was increased obviously（P〈0.05）,and there were significant differences in AUC of two preparations in the Raloxifence Hydrochloride Tablets control group and the compound raloxifence hydrochloride tablets experimental group（P〈0.01）.③The relative bioavailability（Frel）,ie：AUCT·DR/（AUCR·DT）=165.68%.Conclusion：Two groups of agents in rats are in line with a weight of a single-compartment model 1/C2 distribution,and Co.RH tablets can significantly improved the raloxifene relative bioavailability.