新型兽用纳米乳载药系统在大鼠体内的药代动力学研究
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摘要
为了解氟苯尼考纳米乳(FFNE)在大鼠体内药代动力学行为,本试验以氟苯尼考溶液(FFSol)为参比制剂,以30 mg/kg剂量给大鼠灌胃和肌内注射给药,分别于给药后0.5、1、2、4、8、12、24、36、48、72 h采血,利用高效液相色谱法测定血浆中氟苯尼考含量,利用DAS 2.0软件计算房室模型与非房室模型条件下药代动力学参数。结果显示,在两种给药方式下,FFNE与FFSol在大鼠体内均符合二室模型。灌胃给药后,FFNE与FFSol在房室模型条件下AUC_((0-∞))分别为1 085.047和2 176.490 mg/L·h,半衰期分别为10.566和13.687 h,FFNE的相对生物利用度为187.4%。肌内注射给药后,FFNE与FFSol在房室模型条件下AUC_((0-∞))分别为1 530.55和3 243.338 mg/L·h,半衰期分别为7.533和13.335 h,FFNE的相对生物利用度为211.9%。结果表明,FFNE通过灌胃和肌内注射给药在大鼠体内分布较广,灌胃相对肌内注射吸收差,消除快。将氟苯尼考制成纳米乳剂后促进了氟苯尼考的吸收,氟苯尼考的生物利用度显著提高。
To study the pharmacokinetics behavior of florfenicol nanoemulsion in rats,florfenicol solution was chosen as the contrast medicine,the medicine was taken oral and intramuscular dose of 30 mg/kg body weight,and sampled at 0.5,1,2,4,8,12,24,36,48 and 72 h.The concentrations of florfenicol in plasma samples were detected by a high performance liquid chromatography(HPLC) method.The data were analyzed with the pharmacokinetic program DAS 2.0.The results showed that the concentration-time course of florfenicol solution and florfenicol nanoemulsion in plasma fitted a 2-compartment open model.The parameters of FFNE and FFSol under compartmental model after oral administration,AUC_((0-∞)) were 1 085.047 and 2 176.490 mg/L·h,half-life were 10.566 and 13.687 h,the relative bioavailability of florfenicol nanoemulsion was 187.4%.The parameters of FFNE and FFSol under compartmental model after intravenous administration,AUC_((0-∞)) were 1 530.55 and 3 243.338 mg/L·h respectively,the half-life were 7.533 and 13.335 h,respectively,and the relative bioavailability of florfenicol nanoemulsion was 211.9%.The results indicated that FFNE had an adequate distribution in rats after intramscular and oral administration,however,elimination rate was faster by oral administration than by intramuscular of most rats.The prepared florfenicol nanoemulsion promoted absorption of florfenicol,and the bioavailability of florfenicol nanoemulsion was significantly improved.
To study the pharmacokinetics behavior of florfenicol nanoemulsion in rats,florfenicol solution was chosen as the contrast medicine,the medicine was taken oral and intramuscular dose of 30 mg/kg body weight,and sampled at 0.5,1,2,4,8,12,24,36,48 and 72 h.The concentrations of florfenicol in plasma samples were detected by a high performance liquid chromatography(HPLC) method.The data were analyzed with the pharmacokinetic program DAS 2.0.The results showed that the concentration-time course of florfenicol solution and florfenicol nanoemulsion in plasma fitted a 2-compartment open model.The parameters of FFNE and FFSol under compartmental model after oral administration,AUC_((0-∞)) were 1 085.047 and 2 176.490 mg/L·h,half-life were 10.566 and 13.687 h,the relative bioavailability of florfenicol nanoemulsion was 187.4%.The parameters of FFNE and FFSol under compartmental model after intravenous administration,AUC_((0-∞)) were 1 530.55 and 3 243.338 mg/L·h respectively,the half-life were 7.533 and 13.335 h,respectively,and the relative bioavailability of florfenicol nanoemulsion was 211.9%.The results indicated that FFNE had an adequate distribution in rats after intramscular and oral administration,however,elimination rate was faster by oral administration than by intramuscular of most rats.The prepared florfenicol nanoemulsion promoted absorption of florfenicol,and the bioavailability of florfenicol nanoemulsion was significantly improved.
引文
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[15] DOREY L,PELLIGAND L,CHENG Z,et al.Pharmacokinetic/pharmacodynamic integration and modelling of florfenicol for the pig pneumonia pathogens Actinobacillus pleuropneumoniae and Pasteurella multocida[J].PLoS One,2017,12(5):e0177568.
[16] 李艳萍,张志荣.纳米乳的研究进展及其应用[J].华西药学杂志,2010,25(4):485-488. LI Y P,ZHANG Z R.Research progress and application of nano-emulsion[J].West China Journal of Pharmaceutical Sciences,2010,25(4):485-488.(in Chinese)
[17] AGRAWAL N,MADDIKERI G L,PANDIT A B,et al.Sustained release formulations of citronella oil nanoemulsion using cavitational techniques[J].Ultrason Sonochem,2017,36:367-374.
[18] CONG Z,SHI Y,PENG X,et al.Design and optimization of thermosensitive nanoemulsion hydrogel for sustained-release of praziquantel[J].Drug Development and Industrial Pharmacy,2017,43(4):558-573.
[19] 董宏伟,李忠杰,吕淑荣,等.氟苯尼考注射液在大鼠体内代谢及生物利用度研究[J].烟台大学学报(自然科学与工程版),2014,27(2):122-125. DONG H W,LI Z J,LYU S R,et al.Metabolism and bioavailability of florineicol injection in rats[J].Journal of Yantai University (Natural Science and Engineering Edition),2014,27(2):122-125.(in Chinese)
[20] 陈浩娇,郑燕华,竺亚斌,等.新型氟苯尼考药丸的制备及其在大黄鱼体内的药代动力学分析[J].农药学学报,2014,16(3):354-361. CHEN H J,ZHENG Y H,ZHU Y B,et al.Fabrication and in vivo pharmacokinetics of an antibiotic florfenicol pill towards applying in Pseudosciaena crocea fishery[J].Chinese Journal of Pesticide Science,2014,16(3):354-361.(in Chinese)
[21] 杨鹏飞,陈卫东.纳米乳提高难溶性药物生物利用度的研究进展[J].中国药学杂志,2013,48(15):1238-1244. YANG P F,CHEN W D.Research progress of nanoemulsions’ applications in improving the bioavailability of poor water-soluble drugs[J].Chinese Pharmaceutical Journal,2013,48(15):1238-1244.(in Chinese)
[22] LI Y J,HU X B,LU X L,et al.Nanoemulsion-based delivery system for enhanced oral bioavailability and caco-2 cell monolayers permeability of berberine hydrochloride[J].Drug Delivery,2017,24(1):1868-1873.
[23] GAO Y,QI X,ZHENG Y,et al.Nanoemulsion enhances α-tocopherol succinate bioavailability in rats[J].International Journal of Pharmaceutics,2016,515(1-2):506-514.
[2] VARMA K,ADAMS P,POWER S,et al.Pharmacokinetics of florfenicol in veal calves[J].Journal of Veterinary Pharmacology and Therapeutics,1986,9(4):412-425.
[3] SCHWARZ S,KEHRENBERG C,DOUBLT B,et al.Molecular basis of bacterial resistance to chloramphenicol and florfenicol[J].Fems Microbiology Reviews,2004,28(5):519-542.
[4] 张东超,杨宁宁,林静,等.猪传染性胸膜肺炎放线杆菌的分离鉴定及药敏试验[J].中国畜牧兽医,2016,43(6):1604-1609. ZHANG D C,YANG N N,LIN J,et al.Isolation,identification and drug sensitive tests of porcine contagious Actinobacillus pleuropneumoniae[J].China Animal Husbandry & Veterinary Medicine,2016,43(6):1604-1609.(in Chinese)
[5] KHATRI P,SHAO J.Mechanism and structural factors of lipid and surfactant in the formation of self-emulsified nanoemulsion[J].Journal of Pharmaceutical Sciences,2018,107(8):2198-2207.
[6] SINGH Y,MEHER J G,RAVAL K,et al.Nanoemulsion:Concepts,development and applications in drug delivery[J].Journal of Controlled Release,2017,252:28-49.
[7] 时菲菲,秦枫,王秀君,等.氟苯尼考纳米乳制备及其抑菌效果观察[J].中国畜牧兽医,2018,45(10):2936-2942. SHI F F,QIN F,WANG X J,et al.Preparation of florfenicol nanoemulsion and observation of its antibacterial effect[J].China Animal Husbandry & Veterinary Medicine,2018,45(10):2936-2942.(in Chinese)
[8] 白野,陈昆慈,单奇,等.肌注和口灌氟苯尼考在吉富罗非鱼体内的药代动力学[J].淡水渔业,2017,47(4):57-62. BAI Y,CHEN K C,SHAN Q,et al.Study on the pharmacokinetics of florfenicol in tilapia[J].Freshwater Fisheries,2017,47(4):57-62.(in Chinese)
[9] 黄郁葱,汤菊芬,秦青英,等.氟苯尼考在红笛鲷体内的药代动力学研究[J].中国兽药杂志,2016,50(11):58-64. HUANG Y C,TANG J F,QIN Q Y,et al.Pharmacokinetics of florfenicol in Lutjanus sanguineus[J].Chinese Journal of Veterinary Drug,2016,50(11):58-64.(in Chinese)
[10] 李梦影,徐丽娟,吕利群.氟苯尼考在鲫和草鱼体内的药代/药效动力学联合参数及其临床给药方案的研究[J].水产学报,2014,38(6):888-895. LI M Y,XU L J,LYU L Q.Integrated pharmacokinetics/pharmacodynamics parameters of florfenicol in crucian carp (Carassius auratus) and grass carp(Ctenopharyngodon idella) and their significances in drawing medication regimen[J].Journal of Fisheries of China,2014,38(6):888-895.(in Chinese)
[11] YANG F,YANG F,KONG T,et al.Pharmacokinetics of florfenicol and its metabolite florfenicol amine in crucian carp (Carassius auratus) at three temperatures after one single intramuscular injection[J].Journal of Veterinary Pharmacology and Therapeutics,2018,41(5):739-745.
[12] WANG G Y,ZHENG H H,ZHANG K Y,et al.The roles of cytochrome P450 and P-glycoprotein in the pharmacokinetics of florfenicol in chickens[J].Iranian Journal of Veterinary Research,2018,19(1):9-14.
[13] 梅献,万鹏,韩东东,等.肌注氟苯尼考在鸭疫里氏杆菌感染鸭体内的药动学特征[J].中国农业科学,2017,50(20):4021-4027. MEI X,WAN P,HAN D D,et al.Pharmacokinetics of florfenicol in ducks infected with Riemerella anatipestifer after intramuscular administration[J].Scientia Agricultura Sinica,2017,50(20):4021-4027.(in Chinese)
[14] PEREZ R,PALMA C,BRGOS R,et al.The acute phase response induced by Escherichia coli lipopolysaccharide modifies the pharmacokinetics and metabolism of florfenicol in rabbits[J].Journal of Veterinary Pharmacology and Therapeutics,2016,39(2):183-190.
[15] DOREY L,PELLIGAND L,CHENG Z,et al.Pharmacokinetic/pharmacodynamic integration and modelling of florfenicol for the pig pneumonia pathogens Actinobacillus pleuropneumoniae and Pasteurella multocida[J].PLoS One,2017,12(5):e0177568.
[16] 李艳萍,张志荣.纳米乳的研究进展及其应用[J].华西药学杂志,2010,25(4):485-488. LI Y P,ZHANG Z R.Research progress and application of nano-emulsion[J].West China Journal of Pharmaceutical Sciences,2010,25(4):485-488.(in Chinese)
[17] AGRAWAL N,MADDIKERI G L,PANDIT A B,et al.Sustained release formulations of citronella oil nanoemulsion using cavitational techniques[J].Ultrason Sonochem,2017,36:367-374.
[18] CONG Z,SHI Y,PENG X,et al.Design and optimization of thermosensitive nanoemulsion hydrogel for sustained-release of praziquantel[J].Drug Development and Industrial Pharmacy,2017,43(4):558-573.
[19] 董宏伟,李忠杰,吕淑荣,等.氟苯尼考注射液在大鼠体内代谢及生物利用度研究[J].烟台大学学报(自然科学与工程版),2014,27(2):122-125. DONG H W,LI Z J,LYU S R,et al.Metabolism and bioavailability of florineicol injection in rats[J].Journal of Yantai University (Natural Science and Engineering Edition),2014,27(2):122-125.(in Chinese)
[20] 陈浩娇,郑燕华,竺亚斌,等.新型氟苯尼考药丸的制备及其在大黄鱼体内的药代动力学分析[J].农药学学报,2014,16(3):354-361. CHEN H J,ZHENG Y H,ZHU Y B,et al.Fabrication and in vivo pharmacokinetics of an antibiotic florfenicol pill towards applying in Pseudosciaena crocea fishery[J].Chinese Journal of Pesticide Science,2014,16(3):354-361.(in Chinese)
[21] 杨鹏飞,陈卫东.纳米乳提高难溶性药物生物利用度的研究进展[J].中国药学杂志,2013,48(15):1238-1244. YANG P F,CHEN W D.Research progress of nanoemulsions’ applications in improving the bioavailability of poor water-soluble drugs[J].Chinese Pharmaceutical Journal,2013,48(15):1238-1244.(in Chinese)
[22] LI Y J,HU X B,LU X L,et al.Nanoemulsion-based delivery system for enhanced oral bioavailability and caco-2 cell monolayers permeability of berberine hydrochloride[J].Drug Delivery,2017,24(1):1868-1873.
[23] GAO Y,QI X,ZHENG Y,et al.Nanoemulsion enhances α-tocopherol succinate bioavailability in rats[J].International Journal of Pharmaceutics,2016,515(1-2):506-514.