替米考星颗粒在猪体内的药代动力学研究
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摘要
研究20%树脂包被替米考星颗粒在猪体内的药代动力学特性并评价其(受试制剂T)与国际(R1)国内(R2)两种参比制剂的生物等效性。采用随机三制剂、三周期自身交叉试验设计,选取6头健康的阉割过的小公猪(体重20.7±2.6 kg),分别口灌给药三种制剂(10 mg/kg b.w.),采用高效液相色谱法(HPLC)测定血浆替米考星浓度,利用Kinetica 5.0分析药代动力学特性及生物等效性评价。20%树脂包被替米考星颗粒在猪体内的药时曲线符合带一级吸收的二室开放模型;T、R1、R2的C_(max)分别为(0.2830±0.0292)、(0.2815±0.0291)、(0.4087±0.0421)μg/mL,t_(max)分别为(4±0.9832)、(0.75±0.1581)、(1±0.2458)h,AUC_(0-∞)分别为(10.8715±1.1203)、(9.8715±1.0173)、(10.6441±1.096 9)μg·h·mL~(-1);受试制剂相比于两种参比制剂的相对生物利用度分别为110.13±6.04%(R1)和102.63±9.64%(R2)。结果表明,三种制剂间具备生物等效性;20%树脂包被替米考星颗粒有更好的缓释作用,具有一定的生物安全性,在体内保持药效时间更久。
The pharmacokinetics of tilmicosin granula coated with 20% resin(test formulation, T) in swines were investigated and the bioequivalence of T and the other two similar products at home(reference formulation 2, R2) and abroad(reference formulation 1, R1) were also evaluated. A randomized three-period and three-way crossover self-controlled design was employed. Six healthy castrated male pigs(average body weight 20.7±2.6 kg) were selected to take three formulations by oral administration separately(10 mg/kg b.w.). The plasma concentrations of tilmicosin were analyzed by HPLC. The pharmacokinetic parameters and bioequivalence were calculated with Kinetica5.0. The concentration-time curve of tilmicosin granula coated with 20% resin fitted a two-compartment open model with first-order absorption. The main pharmacokinetic parameters of T, R1, R2 were as follows, C_(max) as(0.2830±0.0292),(0.2815±0.0291),(0.4087±0.0421) μg/mL, t_(max) as(4±0.9832),(0.75±0.1581),(1±0.2458)h, AUC_(0-∞) as(10.8715±1.1203),(9.8715±1.0173),(10.6441±1.0969)μg·h·mL~(-1). The relative bioavailability of R1 and R2 were(110.13±6.04)% and(102.63±9.64)%. In conclusion, the three formulations are bioequivalent. Tilmicosin granula coated with 20% resin shows better performance of sustained-release, which improves biosafety and last longer.
The pharmacokinetics of tilmicosin granula coated with 20% resin(test formulation, T) in swines were investigated and the bioequivalence of T and the other two similar products at home(reference formulation 2, R2) and abroad(reference formulation 1, R1) were also evaluated. A randomized three-period and three-way crossover self-controlled design was employed. Six healthy castrated male pigs(average body weight 20.7±2.6 kg) were selected to take three formulations by oral administration separately(10 mg/kg b.w.). The plasma concentrations of tilmicosin were analyzed by HPLC. The pharmacokinetic parameters and bioequivalence were calculated with Kinetica5.0. The concentration-time curve of tilmicosin granula coated with 20% resin fitted a two-compartment open model with first-order absorption. The main pharmacokinetic parameters of T, R1, R2 were as follows, C_(max) as(0.2830±0.0292),(0.2815±0.0291),(0.4087±0.0421) μg/mL, t_(max) as(4±0.9832),(0.75±0.1581),(1±0.2458)h, AUC_(0-∞) as(10.8715±1.1203),(9.8715±1.0173),(10.6441±1.0969)μg·h·mL~(-1). The relative bioavailability of R1 and R2 were(110.13±6.04)% and(102.63±9.64)%. In conclusion, the three formulations are bioequivalent. Tilmicosin granula coated with 20% resin shows better performance of sustained-release, which improves biosafety and last longer.
引文
[1] Backstrom L, Mcdonald J, Collins M. Efficacy of tilmicosin, and a combination of tylosin and sulfamethazine, for control of swine atrophic rhinitis involving infection with toxigenic Pasteurella multocida type D[J]. Journal of Swine Health and Production, 1994, 2(4): 11-14.
[2] Du Y, Yoo D, Paradis M A, et al. Antiviral activity of tilmicosin for type 1 and type 2 porcine reproductive and respiratory syndrome virus in cultured porcine alveolar macrophages[J]. Journal of Antivirals and Antiretrovirals, 2011, 3(3): 28-33.
[3] Shen J, Li C, Jiang H, et al. Pharmacokinetics of tilmicosin after oral administration in swine[J]. American Journal of Veterinary Research, 2005, 66(6): 1071-1074.
[4] 赵林. 替米考星在生猪生产上的应用[J]. 中国猪业, 2012, (5): 60. Zhao L. The application of tilmicosin in swine production[J].Chinese pig industry,2012, (5): 60.
[5] Lin C, Yang Y, Lin W, et al. Tilmicosin reduces PRRSV loads in pigs in vivo[J]. Journal of Agricultural Science, 2015, 8(1): 154.
[6] Rassouli A, Al-qushawi A, Atyabi F, et al. Pharmacokinetics and bioavailability of three promising tilmicosin-loaded lipid nanoparticles in comparison with tilmicosin phosphate following oral administration in broiler chickens[J]. Turkish Journal of Veterinary and Animal Sciences, 2016, 40(5): 540-547.
[7] ICS67.100X16-2007, 牛奶中替米考星残留量的测定高效液相色谱法[M].北京: 中国农业出版社, 2008. ICS67.100X16-2007, A method for determination of tilmicosin residue in milk by high-performance liquid chromatography[M].Beijing:China Agriculture Press,2008
[8] 袁宗辉. 兽药生物等效度试验法[J]. 中国兽药杂志,2002,36(5):36-40. Yuan Z H. Bioequivalence study method of veterinary medicine[J]. China Journal of Veterinary Medicine,2002, 36(5): 36-40.
[9] 沈向荣. 磷酸替米考星在猪体内的药代动力学研究[D]. 南京: 南京农业大学, 2013. Shen X R. Pharmacokinetics of tilmicosin phosphate in swine[D]. Nanjing:Nanjing Agricultural University,2013.
[10] Thomson T D, Buck J M, Moran J W, et al. Pharmacology and safety of Pulmotil (tilmicosin phosphate) in swine[C]//American Association of Swine Practitioners 28th Annual Meeting. Des Moines: ASAP, 1997: 51-55.
[11] 沈向荣, 苏亚楠, 刘彩, 等. 磷酸替米考星在猪体内的药代动力学研究[J]. 南京农业大学学报, 2013, 36(5):120-124. Sheng X R, Su Y N, Liu C, et al. Pharmacokinetics of tilmicosin phosphate in swine[J]. Journal of Nanjing Agricultural University,2013, 36(5): 120-124.
[12] Thomson T D, Darby J M, Moran J W, et al. Serum and lung tilmicosin concentration in swine following dosing with tilmicosin fortified feed[C]//International Pig Veterinary Society Congress. Bangkok: Faculty of Veterinary Science, Chulalongkorn University, 1994: 26-30.
[13] 胡亚南. 氟苯尼考、恩诺沙星及替米考星微囊在猪体内的药物动力学研究[D]. 杨凌: 西北农林科技大学, 2011: 38-52. Hu Y N. Study on the pharmacokinetics of florfenicol,enrofloxacin & tilmicosin microcapsules in pigs[D].Yangling:Northwest A & F University,2011.(in Chinese)
[14] Scorneaux B, Shryock T R. Intracellular accumulation, subcellular distribution and efflux of tilmicosin in swine phagocytes[J]. Journal of Veterinary Pharmacology and Therapeutics, 1998, 21(4): 257-268.
[15] 王建兵. 替米考星溶液和磷酸替米考星可溶性粉在肉鸡体内的药动学比较研究[D]. 扬州: 扬州大学, 2015. Wang J B. Comparative pharmacokinetic of tilmicosin solution and tilmicosin phosphate powder in broilers[D].Yangzhou:Yangzhou University, 2015.
[16] Zhang L, Zhao L, Liu Y, et al. Pharmacokinetics of tilmicosin in healthy pigs and in pigs experimentally infected with Haemophilus parasuis[J]. Journal of Veterinary Science, 2017, 18(4): 431-437.
[17] Puntawee S, Nunta K. Pharmacokinetics of tilmicosin (Resmitil?) in crossbred pigs following single oral administration[J]. Thai Journal of Veterinary Medicine, 2017, 47(Supplementary): 85-87.
[2] Du Y, Yoo D, Paradis M A, et al. Antiviral activity of tilmicosin for type 1 and type 2 porcine reproductive and respiratory syndrome virus in cultured porcine alveolar macrophages[J]. Journal of Antivirals and Antiretrovirals, 2011, 3(3): 28-33.
[3] Shen J, Li C, Jiang H, et al. Pharmacokinetics of tilmicosin after oral administration in swine[J]. American Journal of Veterinary Research, 2005, 66(6): 1071-1074.
[4] 赵林. 替米考星在生猪生产上的应用[J]. 中国猪业, 2012, (5): 60. Zhao L. The application of tilmicosin in swine production[J].Chinese pig industry,2012, (5): 60.
[5] Lin C, Yang Y, Lin W, et al. Tilmicosin reduces PRRSV loads in pigs in vivo[J]. Journal of Agricultural Science, 2015, 8(1): 154.
[6] Rassouli A, Al-qushawi A, Atyabi F, et al. Pharmacokinetics and bioavailability of three promising tilmicosin-loaded lipid nanoparticles in comparison with tilmicosin phosphate following oral administration in broiler chickens[J]. Turkish Journal of Veterinary and Animal Sciences, 2016, 40(5): 540-547.
[7] ICS67.100X16-2007, 牛奶中替米考星残留量的测定高效液相色谱法[M].北京: 中国农业出版社, 2008. ICS67.100X16-2007, A method for determination of tilmicosin residue in milk by high-performance liquid chromatography[M].Beijing:China Agriculture Press,2008
[8] 袁宗辉. 兽药生物等效度试验法[J]. 中国兽药杂志,2002,36(5):36-40. Yuan Z H. Bioequivalence study method of veterinary medicine[J]. China Journal of Veterinary Medicine,2002, 36(5): 36-40.
[9] 沈向荣. 磷酸替米考星在猪体内的药代动力学研究[D]. 南京: 南京农业大学, 2013. Shen X R. Pharmacokinetics of tilmicosin phosphate in swine[D]. Nanjing:Nanjing Agricultural University,2013.
[10] Thomson T D, Buck J M, Moran J W, et al. Pharmacology and safety of Pulmotil (tilmicosin phosphate) in swine[C]//American Association of Swine Practitioners 28th Annual Meeting. Des Moines: ASAP, 1997: 51-55.
[11] 沈向荣, 苏亚楠, 刘彩, 等. 磷酸替米考星在猪体内的药代动力学研究[J]. 南京农业大学学报, 2013, 36(5):120-124. Sheng X R, Su Y N, Liu C, et al. Pharmacokinetics of tilmicosin phosphate in swine[J]. Journal of Nanjing Agricultural University,2013, 36(5): 120-124.
[12] Thomson T D, Darby J M, Moran J W, et al. Serum and lung tilmicosin concentration in swine following dosing with tilmicosin fortified feed[C]//International Pig Veterinary Society Congress. Bangkok: Faculty of Veterinary Science, Chulalongkorn University, 1994: 26-30.
[13] 胡亚南. 氟苯尼考、恩诺沙星及替米考星微囊在猪体内的药物动力学研究[D]. 杨凌: 西北农林科技大学, 2011: 38-52. Hu Y N. Study on the pharmacokinetics of florfenicol,enrofloxacin & tilmicosin microcapsules in pigs[D].Yangling:Northwest A & F University,2011.(in Chinese)
[14] Scorneaux B, Shryock T R. Intracellular accumulation, subcellular distribution and efflux of tilmicosin in swine phagocytes[J]. Journal of Veterinary Pharmacology and Therapeutics, 1998, 21(4): 257-268.
[15] 王建兵. 替米考星溶液和磷酸替米考星可溶性粉在肉鸡体内的药动学比较研究[D]. 扬州: 扬州大学, 2015. Wang J B. Comparative pharmacokinetic of tilmicosin solution and tilmicosin phosphate powder in broilers[D].Yangzhou:Yangzhou University, 2015.
[16] Zhang L, Zhao L, Liu Y, et al. Pharmacokinetics of tilmicosin in healthy pigs and in pigs experimentally infected with Haemophilus parasuis[J]. Journal of Veterinary Science, 2017, 18(4): 431-437.
[17] Puntawee S, Nunta K. Pharmacokinetics of tilmicosin (Resmitil?) in crossbred pigs following single oral administration[J]. Thai Journal of Veterinary Medicine, 2017, 47(Supplementary): 85-87.