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[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ACQUITY UPLC HSS T3 1.8 μm(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0.3 mL/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,Cmax为(2 148.22±448.5) ng/mL,AUC0-t为(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0.09 h,与iv给药相当,而Cmax(231.54±177.19) ng/mL和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Cmax为(1 958.34±1 209.41) ng/mL,AUC0-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。
[Key word]
[Abstract]
Objective Investigate the pharmacokinetics of erythromycin cyclic 11, 12-car-bonate 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 bioavailability improvement of erythromycin cyclic 11, 12-car-bonate nanocrystals for pulmonary administration was evaluated. Results The chromatographic column was ACQUITY UPLC HSS T3 1.8 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, Cmax was (2 148.22 ±448.5) ng/mL, AUC0-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. Cmax (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 bioavailability 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 Cmax and AUC0-t of lung administration were (1 958.34 ±1 209.41) ng/mL and (773.11 ±473.49) h·μg/ mL, which were equivalent to iv administration, but significantly higher than API of lung administration (P < 0.05); the absolute bioavailability was 117.10%. Conclusion After pulmonary administration in rats, the bioavailability of erythromycin cyclic 11,12-car-bonate nanocrystals can be significantly improved, suggesting the feasibility of erythromycin cyclic 11, 12-car-bonate for pulmonary preparations.
[中图分类号]
R969.1
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