柔性玉米醇溶蛋白纳米颗粒负载大麻二酚药代动力学研究  

Study on the pharmacokinetics of cannabidiol supported by flexible zein nanoparticles

作　　者：孔艳 焦玥[1] 彭娟[1] 吴晓霞[1] 聂颖兰[1] 范斌[1] KONG Yan;JIAO Yue;PENG Juan;WU Xiao-xia;NIE Ying-lan;FAN Bin(Beijing Key Laboratory of Traditional Chinese Medicine Basic Research on Prevention and Treatment of Major Diseases,Experimental Research Center,China Academy of Chinese Medical Sciences,Beijing 100700,China)

机构地区：[1]中国中医科学院医学实验中心,北京市中医药防治重大疾病基础研究重点实验室,北京100700

出　　处：《药物分析杂志》2023年第10期1718-1726,共9页Chinese Journal of Pharmaceutical Analysis

基　　金：自然科学基金培育专项(JJPY2022007);国家自然科学基金青年科学基金项目(82104391);山东省泰山学者青年专家项目(tsqn202211360)。

摘　　要：目的:通过对负载大麻二酚(CBD)的柔性玉米醇溶蛋白纳米颗粒(FZP-CBD)和负载CBD的天然玉米醇溶蛋白纳米颗粒(NZP-CBD)在正常大鼠体内药代动力学研究,比较二者生物利用度的差异。方法:采用反溶剂法制备FZP-CBD和NZP-CBD,SD大鼠灌胃给予2组纳米制剂(CBD低、中、高3个剂量分别为20、50、100 mg·kg^(-1)),在给药前及给药后0.5、1、1.5、2、3、4、6、8、10、12、24、48 h眼眶静脉丛采血,采用高效液相色谱-串联质谱法(HPLC-MS法)测定大鼠体内CBD的浓度,采用Waters Atlantis T3(100 mm×2.1 mm,3μm)色谱柱;以0.1%甲酸水溶液为流动相A,0.1%甲酸乙腈溶液为流动相B,梯度洗脱;流速0.3 mL·min-1;柱温30℃;进样量1μL;检测以电喷雾电离源(ESI),正离子模式扫描,多反应监测模式(MRM)进行;用Winnonlin 8.1软件计算药动学相关参数。结果:FZP-CBD和NZP-CBD低、中、高3个剂量的C_(max)分别为(414.8±184.1)、(715.3±191.7)、(1798.4±854.5)和(240.6±143.8)、(542.3±235.4)、(1173.3±317.0)μg·L^(-1),AUC_(0-t)分别为(1955.2±632.9)、(7255.2±1573.8)、(26634.0±16479.7)和(1438.6±557.1)、(6316.5±2916.3)、(15674.1±4365.7)μg·h·L^(-1);与NZP-CBD相比,FZP-CBD低、中、高3个浓度C_(max)分别提高了1.7、1.3、1.5倍,AUC_(0-t)分别提高了1.4、1.1、1.7倍,生物利用度(F)分别提高了135.9%、114.9%、169.6%。结论:LC-MS测定方法专属性、灵敏度均能满足大鼠血清药动学测定。利用酸修饰制备的FZP-CBD相比NZP-CBD提高了CBD生物利用度,本研究可以提高CBD的利用价值,为CBD在医药学中的应用提供了新思路。Objective:To compare the difference on the bioavailability between cannabidiol(CBD)-loaded flexible zein nanoparticles(FZP-CBD)and CBD-loaded natural zein nanoparticles(NZP-CBD)by investigating the pharmacokinetics of both in normal rats.Methods:FZP-CBD and NZP-CBD were prepared by inverse-solvent method.SD rats were administrated with two groups of nano-preparations(the low,medium and high doses of CBD were 20,50 and 100 mg·kg^(-1),respectively)by intragastric administration.Blood samples were collected from orbital venous plexus before and at 0.5,1,1.5,2,3,4,6,8,10,12,24,48 h after administration.The concentrations of CBD were determined by high-performance liquid chromatography-tandem mass spectrometry(HPLC-MS),using Waters Atlantis T3(100 mm×2.1 mm,3μm)column,0.1% formic acid-water as mobile phase A,0.1% formic acid-acetonitrile as mobile phase B,gradient elution,at a flow rate of 0.3 mL·min^(-1),the column temperature was 30℃and the injection volume was 1μL.The detection was carried out by electrospray ionization source(ESI),positive ion mode scanning and multiple reaction monitoring(MRM)mode.Winnonlin 8.1 software was used to calculate the pharmacokinetic parameters.Results:The C_(max)of low,medium and high concentration of FZP-CBD and NZP-CBD were(414.8±184.1)μg·L^(-1),(715.3±191.7)μg·L^(-1),(1798.4±854.5)μg·L^(-1)and(240.6±143.8)μg·L^(-1),(542.3±235.4)μg·L^(-1),(1173.3±317.0)μg·L^(-1),respectively.AUC_(0-t)were(1955.2±632.9)μg·h·L^(-1),(7255.2±1573.8)μg·h·L^(-1),(26634.0±16479.7)μg·h·L^(-1)and(1438.6±557.1)μg·h·L^(-1),(6316.5±2916.3)μg·h·L^(-1),(15674.1±4365.7)μg·h·L^(-1),respectively.Compared with NZP-CBD,the C_(max)of low,medium and high concentration of FZP-CBD increased by 1.7,1.3 and 1.5 times respectively,and AUC_(0-t)increased by 1.4,1.1 and 1.7 times respectively,bioavailability(F)increased by 135.9%,114.9%,169.6% respectively.Conclusion:The specificity and sensitivity of LC-MS assay can satisfy the pharmacokinetic determination of rat serum.Compare

关 键 词：玉米醇溶蛋白 大麻二酚 药代动力学 血药浓度 大鼠血清 生物利用度 高效液相色谱-串联质谱法 

分 类 号：R917[医药卫生—药物分析学]