蝙蝠葛碱自微乳化释药系统在大鼠体内的生物利用度研究
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摘要
目的:研究蝙蝠葛碱自微乳化释药系统(SMEDDS)在大鼠体内的相对生物利用度。方法:12只大鼠随机分为蝙蝠葛碱SMEDDS组(20 mg/kg)和蝙蝠葛碱溶液组(50 mg/kg),每组6只,ig相应药物。分别于给药前和给药后0.167、0.333、0.5、0.75、1、2、4、8、12、24、36 h由眼眶后静脉丛取血约0.3 ml,采用高效液相色谱-串联质谱法测定血浆中蝙蝠葛碱浓度,采用DAS 3.0软件计算药动学参数,评价蝙蝠葛碱SMEDDS给药后蝙蝠葛碱的相对生物利用度。结果:大鼠血浆中蝙蝠葛碱质量浓度的线性范围为2.12~424 ng/ml(r=0.999 9),日内、日间RSD均小于10%。蝙蝠葛碱溶液和蝙蝠葛碱SMEDDS组大鼠药动学参数c_(max)分别为(126.3±37.4)、(179.6±51.5)ng/ml,t_(1/2)分别为(11.48±4.58)、(21.79±6.59)h,AUC_(0-t)分别为(1 963.5±638.3)、(2 535.8±739.5)ng·h/ml,AUC_(0-∞)分别为(2 256.3±703.5)、(2 854.6±768.7)ng·h/ml;分别以AUC_(0-t)和AUC_(0-∞)计算,蝙蝠葛碱SMEDDS的相对生物利用度分别为323%和316%。结论:ig蝙蝠葛碱SMEDDS后可以显著提高蝙蝠葛碱的相对生物利用度。
OBJECTIVE:To study relative bioavailability of dauricine self-microemulsifying drug delivery system(SMEDDS)in rats.METHODS:12 rats were randomly divided into dauricine SMEDDS group(20 mg/kg)and dauricine solution group(50mg/kg),6 rats in each group.They were given relevant medicine intragastrically.Then,0.3 ml plasma was collected from orbital venous plexus before medication and 0.167,0.333,0.5,0.75,1,2,4,8,12,24,36 h after medication.The plasma concentration of da- uricine was determined by HPLC-MS/MS,and DAS 3.0 was used to calculate pharmacokinetic parameters and evaluate the relative bioavailability of dauricine with dauricine SMEDDS.RESULTS:The linear range of dauricine in plasma were 2.12-424 ng/ml(r=0.999 9);RSDs of intra-day and inter-day were all lower than 10%.Pharmacokinetic parameters of dauricine solution and dauricine SMEDDS were that c_(max)were(126.3±37.4)ng/ml and(179.6±51.5)ng/ml;t_(1/2)were(11.48±4.58)and(21.79±6.59)h;AUC_(0-t)were(1 963.5±638.3)ng·h/ml and(2 535.8±739.5)ng·h/ml;AUC_(0-∞)were(2 256.3±703.5)ng·h/ml and(2 854.6±768.7)ng·h/ml,respectively.The relative bioavailability of dauricine SMEDDS were 323% and 316% by calculating with AUC_(0-t) and AUC0- ∞,respectively.CONCLUSIONS:Intragastric administration of dauricine SMEDDS can improve relative bioavailability of dauricine significantly.
OBJECTIVE:To study relative bioavailability of dauricine self-microemulsifying drug delivery system(SMEDDS)in rats.METHODS:12 rats were randomly divided into dauricine SMEDDS group(20 mg/kg)and dauricine solution group(50mg/kg),6 rats in each group.They were given relevant medicine intragastrically.Then,0.3 ml plasma was collected from orbital venous plexus before medication and 0.167,0.333,0.5,0.75,1,2,4,8,12,24,36 h after medication.The plasma concentration of da- uricine was determined by HPLC-MS/MS,and DAS 3.0 was used to calculate pharmacokinetic parameters and evaluate the relative bioavailability of dauricine with dauricine SMEDDS.RESULTS:The linear range of dauricine in plasma were 2.12-424 ng/ml(r=0.999 9);RSDs of intra-day and inter-day were all lower than 10%.Pharmacokinetic parameters of dauricine solution and dauricine SMEDDS were that c_(max)were(126.3±37.4)ng/ml and(179.6±51.5)ng/ml;t_(1/2)were(11.48±4.58)and(21.79±6.59)h;AUC_(0-t)were(1 963.5±638.3)ng·h/ml and(2 535.8±739.5)ng·h/ml;AUC_(0-∞)were(2 256.3±703.5)ng·h/ml and(2 854.6±768.7)ng·h/ml,respectively.The relative bioavailability of dauricine SMEDDS were 323% and 316% by calculating with AUC_(0-t) and AUC0- ∞,respectively.CONCLUSIONS:Intragastric administration of dauricine SMEDDS can improve relative bioavailability of dauricine significantly.
引文
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[12]高秀蓉,蒋学华,杜青青.基于Caco-2细胞模型研究蝙蝠葛碱的跨膜吸收机制[J].中国实验方剂学杂志,2012,18(15):139.
[13]高秀蓉,蒋学华,王凌,等.基于大鼠在体单向肠灌流模型研究P糖蛋白抑制剂对蝙蝠葛碱肠吸收的影响[J].中国医院药学杂志,2012,32(13):1 016.
[14]Zvonar A,Berginc K,Kristl A,et al.Microencapsulation of self-microemulsifying system:improving solubility and permeability of furosemide[J].Int J Pharm,2010,388(1):151.
[2]Yang XY,Liu QN,Zhang L,et al.Neuroprotective effect of dauricine after transient middle cerebral artery occlusion in rats:involvement of Bcl-2 family proteins[J].Am J Chinese Med,2010,38(2):307.
[3]Wang J,Li Y,Zu XB,et al.Dauricine can inhibit the activity of proliferation of urinary tract tumor cells[J].Asian Pac J Trop Med,2012,5(12):973.
[4]Gao X,Jiang X,Wang L.Using LC-MS/MS to study dauricine pharmacokinetics and determine its bioavailability following administration in different routes[J].Acta Chromatogr,2013,25(2):241.
[5]Chen ZQ,Liu Y,Zhao JH,et al.Improved oral bioavailability of poorly water-soluble indirubin by a supersaturatable self-microemulsifying drug delivery system[J].Int J Nanomed,2012,doi:10.2147/IJN.S28761.
[6]Wu X,Xu J,Huang X,et al.Self-microemulsifying drug delivery system improves curcumin dissolution and bioavailability[J].Drug Dev Ind Pharm,2011,37(1):15.
[7]Hintzen F,Perera G,Hauptstein S,et al.In vivo evaluation of an oral self-microemulsifying drug delivery system(SMEDDS)for leuprorelin[J].Int J Pharm,2014,472(1):20.
[8]Sha X,Wu J,Chen Y,et al.Self-microemulsifying drugdelivery system for improved oral bioavailability of probucol:preparation and evaluation[J].Int J Nanomed,2012,doi:10.2147/IJN.S28052.
[9]张亚红,王娟,甘淋玲,等.蝙蝠葛碱自微乳化释药系统的制备及质量评价[J].中国药房,2015,26(16):2 269.
[10]张亚红,唐倩,刘耀,等.自微乳化给药系统提高蒿甲醚大鼠的口服生物利用度[J].第三军医大学学报,2014,36(14):1 481.
[11]陈淑娟,庞雪冰.蝙蝠葛碱大鼠体内药物代谢动力学研究[J].中国药理学通报,2001,17(2):225.
[12]高秀蓉,蒋学华,杜青青.基于Caco-2细胞模型研究蝙蝠葛碱的跨膜吸收机制[J].中国实验方剂学杂志,2012,18(15):139.
[13]高秀蓉,蒋学华,王凌,等.基于大鼠在体单向肠灌流模型研究P糖蛋白抑制剂对蝙蝠葛碱肠吸收的影响[J].中国医院药学杂志,2012,32(13):1 016.
[14]Zvonar A,Berginc K,Kristl A,et al.Microencapsulation of self-microemulsifying system:improving solubility and permeability of furosemide[J].Int J Pharm,2010,388(1):151.