季铵化程度对N-三甲基壳聚糖包衣溴吡斯的明脂质体兔体内药动学的影响研究

Effect of Quaternization Degree on Pharmacokinetics of N-trimethyl Chitosan-coated Pyridostigmine Bromide Liposomes in Rabbits

目的:研究N-三甲基壳聚糖(TMC)的季铵化程度(QD)对TMC包衣溴吡斯的明(PB)脂质体(PBL)在兔体内药动学的影响。方法:采用逆向蒸发法制备PBL,以QD分别为20%、40%及60%的TMC(TMC20、TMC40及TMC60)对PBL进行包衣。30只日本大耳白兔随机分成5组,采用自身交叉对照实验,分别单剂量口服TMC20、TMC40及TMC60包衣PBL、未包衣PBL及市售PB普通片,HPLC法测定血浆中PB的浓度,用DAS 2.1.1软件计算药动学参数和各种TMC包衣PBL及未包衣PBL的相对生物利用度。结果:TMC20、TMC40及TMC60包衣PBL、未包衣PBL及市售PB普通片在兔体内的药动学特征均符合二室模型,主要药动学参数:C_(max)分别为(15.23±0.12),(15.20±0.22),(15.13±0.24),(15.43±0.51)和(17.60±0.48)mg·L^(-1);t_(max)分别为(4.16±0.10),(4.28±0.17),(4.52±0.24),(4.05±0.15)和(2.33±0.28)h;AUC_(0-x)分别为(233.42±3.88),(239.78±3.68),(252.93±5.01),(222.64±4.24)和(196.55±2.98)mg·h·L^(-1)。与市售PB片相比,TMC20、TMC40及TMC60包衣PBL、未包衣PBL的相对生物利用度分别为118.76%,121.99%,128.68%,113.27%。经方差分析、双单侧t检验和非参数检验,与市售普通片相比,TMC40、TMC60包衣PBL生物利用度显著提高(P<0.05),而TMC20包衣PBL及未包衣PBL则无明显变化(P>0.05)。结论:TMC包衣PBL可显著提高药物兔体内生物利用度,QD对其有显著性影响,随着QD的增大,TMC包衣PBL生物利用度逐渐增大。

Objective ： To study the＇effect of quaternization degree （QD） of N-trimethyl ehitosan （ TMC ） on pharmaeokineties of TMC-coated pyfidostigmine bromide liposomes （PBL） in rabbits. Method： PBL were prepared by reverse phase evaporation followed by TMC coating with QD of 20%, 40% and 60% （TMC20, TMC40 and TMCr0）, respectively. Thirty Japanese rabbits were random- ly divided into five groups. Based on the self-crossover control experiment, the rabbits were subjected to single-dose oral administration of the three TMC-eoated PBL, uncoated PBL and the marketed PB tablets, respectively. The PB concentrations in the rabbit plasma were determined by HPLC, and the DAS 2.1.1 software was applied to calculate the pharmacokinetic parameters and relative bioavail- ability of TMC-coated PBL and uncoated PBL. Result ： The pharmacokinetic property of TMC20-coated PBL, TMC40-coated PBL, TMC60-coated PBL, uncoated PBL and the marketed PB tablets were all fitted two-compartment model with the main pharmacokinetic parameters as follows ： Cm~~ of（ 15.23 ~ 0.12 ）, （ 15.20 -＋ 0.22 ）, （ 15.13 ~ O. 24 ）, （ 15.43 ＋ 0.51 ） and （ 17.60 ＋ 0.48 ）mg ~ L - 1 ; t~,~ of （4.16 ~0.10）, （4.28 -＋0.17）, （4. 52 ~0.24.）, （4.05 ~0.15） and（2.33 ~0.28）h;AUCo_~ of （233.42 -＋3.88）, （239.78 -＋ 3.68 ）, （ 252.93 -＋ 5.01 ）, （222.64 -＋ 4.24） and （ 196.55 -＋ 2.98 ）mg h L- 1. Compared with the marketed PB tablets, the relative bioavailability of TMC20-coated PBL, TMC40-coated PBL, TMC60-coated PBL and uncoated PBL was 118.76%, 121.99%, 128. 68% and 113.27%, respectively. Through variance analysis, two one sided t-test and nonparametric test, the bioavailability of TMCA0-eoated PBL and TMC60-coated PBL was increased significantly （ P 〈 0.05 ）, while that of TMC20-coated PBL and uncoated PBL showed no notable difference （P 〉 O. 05 ） suggesting bioequivalenee. Conclusion： TMC coating can enhance the bioavailability of PBL significantly, and QD of TMC shows notable effect on the bioavailability of PBL in rabbits.