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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。
AIM: To investigate the effect of quaternization (QD) of N-trimethyl chitosan (TMC) on the pharmacokinetics of TMC coated PBM liposomes in rabbits. Methods: PBLs were prepared by reverse evaporation and PBLs were coated with TMCs (TMC20, TMC40 and TMC60) with QD of 20%, 40% and 60%, respectively. Thirty Japanese white rabbits were randomly divided into 5 groups. Their own cross-over control experiments were used to test the concentration of PB in plasma by single oral dose of TMC20, TMC40 and TMC60 coated PBL, uncoated PBL and commercially available PB ordinary tablets respectively , The relative bioavailability of pharmacokinetic parameters and various TMC coated PBLs and uncoated PBLs were calculated using the DAS 2.1.1 software. Results: The pharmacokinetic characteristics of TMC20, TMC40 and TMC60 coated PBL, uncoated PBL and commercial PB were in accordance with the two-compartment model. The main pharmacokinetic parameters were: C max (15.23 ± (4.16 ± 0.10), (4.28 ± 0.22), (15.20 ± 0.22), (15.13 ± 0.24), (15.43 ± 0.51) and (17.60 ± 0.48) mg · L -1, respectively AUC0-x were (233.42 ± 3.88), (239.78 ± 3.68), (252.93 ± 5.01), (222.64), (4.52 ± 0.24), (4.05 ± 0.15) ± 4.24) and (196.55 ± 2.98) mg · h · L -1, respectively. Compared with the commercially available PB tablets, the relative bioavailability of TMC20, TMC40 and TMC60 coated PBL and uncoated PBL were 118.76%, 121.99%, 128.68% and 113.27% respectively. By means of analysis of variance, double unilateral t-test and non-parametric test, the bioavailability of TMC40 and TMC60 coated PBLs was significantly increased (P <0.05) compared with the commercial tablets, while TMC20-coated PBLs and uncoated PBLs No significant change (P> 0.05). Conclusion: TMC-coated PBL can significantly improve the bioavailability of rabbits in vivo. QD has a significant effect on it. With the increase of QD, the bioavailability of TMC-coated PBL gradually increases.