环酯红霉素纳米晶的大鼠肺部喷雾给药药动学研究  

Pharmacokinetics of erythromycin cyclic 11,12-car-bonate nanocrystals pulmonary administration

作　　者：张路丹 卢鹏 皮佳鑫[1,2] 闫宏丽 张瀛[1,2] 谢佳蓉 刘志东 ZHANG Ludan;LU Peng;PI Jiaxin;YAN Hongli;ZHANG Ying;XIE Jiarong;LIU Zhidong(Institute of Traditional Chinese Medicine,Tianjin University of Traditional Chinese Medicine,Tianjin 301600,China;Engineering Center of Modern Chinese Medicine Discovery And Preparation Technology,Ministry of Education,Tianjin University of Traditional Chinese Medicine,Tianjin 301600,China)

机构地区：[1]天津中医药大学中医药研究院,天津301600 [2]天津中医药大学现代中药发现与制剂技术教育部工程中心,天津301600

出　　处：《药物评价研究》2021年第4期762-766,共5页Drug Evaluation Research

摘　　要：目的研究环酯红霉素纳米晶肺部给药的药动学,考察其肺部给药特点。方法建立液相色谱-串联质谱(LC-MS/MS)法检测环酯红霉素血药浓度,并进行专属性、精密度、准确度和稳定性、提取回收率考察;SD大鼠随机分为3组,分别以15 mg/kg iv环酯红霉素注射液、肺部喷雾给予环酯红霉素原料药和环酯红霉素纳米混悬液,于给药后0.033、0.083、0.167、0.25、0.5、0.75、1、1.5、2、3、4、6、8 h眼眶取血,检测大鼠血浆中环酯红霉素的含量,评价纳米晶对环酯红霉素肺部给药药动学、生物利用度的影响。结果色谱柱为ACQUITYUPLC HSS T31.8μm(100 mm×2.1 mm);流动相为5 mmol/L乙酸铵溶液(0.02%甲酸)-甲醇(0.02%甲酸)(85:15);体积流量0.3mL/min;采用电喷雾离子源(ESI),正离子模式多反应监测(MRM),建立的LC-MS/MS分析方法符合方法学要求。环酯红霉素以15 mg/kg iv给药后,达峰时间为0.03 h,C_(max)为(2148.22±448.5)ng/mL,AUC0-t(660.21±96.47)h·μg/mL。环酯红霉素原料药肺部给药后,达峰时间为0.09h,与iv给药相当,而C_(max)(231.54±177.19)ng/mL和AUC_(0-t)(29.37±27.08)h·μg/mL较iv组显著降低(P<0.05),其绝对生物利用度仅为3.72%。纳米晶肺部给药后,达峰时间为0.14 h,与原料药iv给药相比显著延长(P<0.05);纳米晶肺部给药的C_(max)为(1958.34±1209.41)ng/mL,AUC_(0-t)为(773.11±473.49)h·μg/mL,均与iv给药相当,而显著高于原料药肺部给药(P<0.05);其绝对生物利用度为117.10%。结论大鼠肺部给药环酯红霉素纳米晶后可明显提高环酯红霉素的生物利用度,提示纳米晶用于肺部制剂的可行性。Objective Investigate the pharmacokinetics of erythromycin cyclic 11,12-car-borate nanocrystals for pulmonary administration and investigate the characteristics of pulmonary administration.Methods A liquid chromatography tandem mass spectrometry(LC-MS/MS)method was established for the determination of erythromycin cyclic 11,12-car-bonate in human plasma,the specificity,precision,accuracy and stability,extraction recovery were investigated.SD rats were was injected 15 mg/kg of erythromycin cyclic 11,12-car-bonate.At the same time,15 mg/kg of pure drug and nanocrystals were delivered by the lungs.Blood was taken from the orbit at 0.033,0.083,0.167,0.25,0.5,0.75,1,1.5,2,3,4,6,8 h after administration,and the level of erythromycin cyclic 11,12-car-bonate content in the rat plasma was measured.By analyzing the pharmacokinetics,the bio availability improvement of erythromycin cyclic 11,12-car-bonate nanocrystals for pulmonary administration was evaluated.Results The chromatographic column was ACQUITY UPLC HSS T31.8 m(100 mm×2.1 mm);the mobile phase was 5 mmol/L ammonium acetate solution(0.02% formic acid)-methanol(0.02% formic acid)(85:15);volume flow 0.3 mL/min;electrospray ion source(ESI),positive ion mode multi reaction monitoring(MRM).The methodology tests of LC-MS/MS was all for compliance with the test requirements.The peak time was 0.03 h,C_(max) was(2148.22±448.5)ng/mL,AUC_(0-t) was(660.21±96.47)h·μg/mL of erythromycin cyclic 11,12-car-bonate iv group.After lung administration,the peak time of erythromycin cyclamate was 0.09 h,which was equivalent to iv administration,C_(max)(231.54±177.19)ng/mL and AUC0-t(29.37±27.08)h·μg/mL were significantly lower than those in iv administration group(P<0.05),and its absolute bio availability was only 3.72%.After erythromycin cyclic 11,12-car-bonate nanocrystals lung administration,the peak time was 0.14 h,which was significantly longer than that of iv administration(P<0.05);the C_(max) and AUC_(0-t) of lung administration were(1958.34±1209.41)ng/mL and(773.11±473

关 键 词：环酯红霉素 纳米晶 肺部喷雾 液相色谱-串联质谱 药动学 生物利用度 

分 类 号：R969.1[医药卫生—药理学]