十取代芦丁硫酸钠药动学和血浆蛋白结合率研究(英文)

Pharmacokinetics and plasma protein binding of rutin deca (H-) sulfate sodium

十取代芦丁硫酸钠(RDS)作为一种补体免疫抑制剂对恒温动物和人类免疫缺陷病毒(HIV)具有很高活性。本文采用离子对固相萃取技术(IP-SPE)从大鼠血浆、尿液、胆汁和蛋白溶液中分离提取十取代芦丁硫酸钠,并考察了十取代芦丁硫酸钠静脉注射后的药动学参数、排泄(包括尿液和胆汁)和蛋白结合情况。大鼠尾静脉注射给药3个剂量(5、20和100mg·kg?1)后,药-时曲线数据用药动学软件进行拟合,符合静脉注射二室模型,平均消除半衰期t1/2β为3.432±0.1852h,并且给药剂量与AUC具有良好的线性关系,药动学参数与给药剂量无关,提示十取代芦丁硫酸钠在大鼠体内的处置情况属于线性动力学。大鼠尾静脉注射十取代芦丁硫酸钠(20mg·kg?1)后,尿液和胆汁的累积排泄率分别为86.0%±6.1%和0.3181%±0.2087%。十取代芦丁硫酸钠与SD大鼠、Beagle犬和人血浆蛋白结合率为80%～90%,与HSA为85.7%±1.3%,而与人α1-AGP则为14.0%±3.2%,两者之间有极显著性差异(P<0.001)。

Rutin deca （H-） sulfate sodium （RDS） possesses very good activity as an inhibitor of the complement system of warm-blooded animals and HIV. An ion-pair coupled with solid-phase extraction technique （IP-SPE） was developed to extract RDS from rat plasma, urine, bile and protein solution samples. The assay was applied to pharmacokinetics of RDS, including plasma pharmacokinetics, excretion and protein binding studies. After iv 5, 20 and 100 mg·kg^-1 RDS via tail vein in rats, the plasma concentration-time profiles were fitted using 3P97 software. The average terminal half-life （t1/2） was 3.432 ± 0.185 2 h. The relationship of dose and AUC of RDS was linear within the dosage range. This suggested that the disposition of RDS in rats belong to linear kinetics and the pharmacokinetic parameters of RDS were dose independent. After iv RDS 20 mg·kg^-1 in rats, the biliary excretion amount of parent drug amount was only 0.318 1% ± 0.208 7% of given dosage, and the urinary excretion was 86.0% ± 6.1% in 36 h. Ultrafiltration techniques were applied to determine the protein binding of RDS in plasma （from SD rat, Beagle dog and human）, human serum albumin （HSA） and human α1-acid glycoprotein （AGP）. The mean protein binding rate in plasma of SD rat, Beagle dog and human plasma of RDS were 80%-90%, in which the range of concentration of RDS was 5 to 100 μg·mL-1. The protein binding to HSA was 85.7% ± 1.3% and 14.0% ± 3.2% to AGP.