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目的研究载天冬酰胺酶(asparaginase,AAS)自组装透明质酸-聚乙二醇(hyaluronic acid-graft-poly ethylene glycol,HA-g-PEG)/羟丙基-β-环糊精(hydroxypropyl-beta-cyclodextrin,HPCD)纳米微球(self-assembly HA-gPEG/HPCD hollow nanospheres loaded with AAS,AHHPs)在雄性SD大鼠体内的药代动力学和生物等效性。方法采用自组装方法制备AHHPs,考察AHHPs的透射电镜、粒径、Zeta电位、包封率,分别测定大鼠静脉注射给予AHHPs和游离AAS后,不同时间点大鼠血浆样品中AAS的活性。采用DAS 2.1.1软件计算药动学参数,对AHHPs和游离AAS进行生物等效性评价。结果制得的AHHPs平均粒径为(367.43±2.72)nm,Zeta电位为(-15.70±1.25)mV,平均包封率为(66.03±3.81)%。AHHPs和游离AAS大鼠静脉注射给药后,AHHPs和游离AAS的主要药动学参数:药时曲线下面积AUC(0-48h)分别为(162.06±4.01)U/mL·h和(46.38±1.98)U/mL·h,AUC(0-∞)分别为(203.74±12.91)U/mL·h和(51.44±3.01)U/mL·h,平均驻留时间MRT(0-72h)分别为(4.35±0.06)h和(1.76±0.06)h,MRT(0-∞)分别为(7.53±1.05)h和(2.44±0.29)h,药峰浓度Cmax分别为(30.37±0.43)U/mL和(26.06±0.88)U/mL,达峰时间Tmax分别为(0.75±0.00)h和(0.08±0.00)h。与游离AAS比较,AHHPs的AUC(0-48h)、AUC(0-∞)、MRT(0-72h)、MRT(0-∞)、Cmax和Tmax分别提高了3.5倍、4.0倍、2.5倍、3.1倍、1.2倍和9.4倍。AUC(0-48h)、AUC(0-∞)和Cmax的90%置信区间分别为72.6%~74.0%、72.3%~73.7%、94.7%~96.3%。结论AHHPs延长了AAS在大鼠体内的生物半衰期,提高了AAS在大鼠体内的生物利用度,且AHHPs与游离AAS不具有生物等效性。
OBJECTIVE To study the effect of asparaginase-loaded self-assembled hyaluronic acid-graft-poly ethylene glycol (HA-g-PEG) / hydroxypropyl- Pharmacokinetics and bioequivalence of self-assembly HA-gPEG / HPCD hollow nanospheres loaded with AAS (AHHPs) in male SD rats. Methods AHHPs were prepared by self-assembly method. The transmission electron microscopy, particle size, Zeta potential and entrapment efficiency of AHHPs were investigated. The activity of AAS in plasma of rats at different time points was measured after intravenous administration of AHHPs and free AAS. The pharmacokinetic parameters were calculated using DAS 2.1.1 software and the bioequivalence of AHHPs and free AAS was evaluated. Results The average diameter of AHHPs was (367.43 ± 2.72) nm and the zeta potential was (-15.70 ± 1.25) mV. The average entrapment efficiency of AHHPs was (66.03 ± 3.81)%. The pharmacokinetic parameters of AHHPs and free AAS after AHHPs and free AAS rats were administered intravenously were as follows: the area under the curve of AUC (0-48h) were (162.06 ± 4.01) U / mL · h and (46.38 ± 1.98) U / mL · h and AUC (0-∞) were (203.74 ± 12.91) U / mL · h and (51.44 ± 3.01) U / mL · h, respectively. Mean residence time MRT (4.35 ± 0.06) h and (1.76 ± 0.06) h, MRT (0-∞) were (7.53 ± 1.05) h and (2.44 ± 0.29) h, respectively, and peak drug concentration Cmax were (30.37 ± 0.43) U / mL And (26.06 ± 0.88) U / mL, respectively. The peak time Tmax was (0.75 ± 0.00) h and (0.08 ± 0.00) h, respectively. The AUC (0-48h), AUC (0-∞), MRT (0-72h), MRT (0-∞), Cmax and Tmax of AHHPs were increased 3.5 times, 4.0 times, 2.5 times, 3.1 times, 1.2 times and 9.4 times. The 90% confidence intervals of AUC (0-48h), AUC (0-∞) and Cmax were 72.6% -74.0%, 72.3% -73.7% and 94.7% -96.3%, respectively. Conclusions AHHPs prolong the biological half-life of AAS in rats and improve the bioavailability of AAS in rats. AHHPs are not bioequivalent to free AAS.