特比萘芬在比格犬体内的药动学和绝对生物利用度
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摘要
8只健康比格犬采用随机交叉试验设计,盐酸特比萘芬注射液按5 mg/kg单剂量静注,盐酸特比萘芬片按20mg/kg单剂量口服给药,洗脱期为2周。采用高效液相色谱法测定犬血浆中特比萘芬的浓度,以药动学分析软件WinNonlin5.2的非房室模型分析方法处理血药浓度-时间数据。结果显示,犬静注盐酸特比萘芬注射液的药动学参数分别为:Tmax(0.083±0.000)h,Cmax(3.334±0.185)mg/L,T1/2β(15.158±8.558)h,MRT(2.443±1.132)h,AUClast(1.803±0.374)h·mg/L,Vd(49 778.164±25 594.370)mL/kg,CLB(2 414.907±577.369)kg·mL/h。犬口服盐酸特比萘芬片的主要药动学参数为:Tmax(1.875±0.791)h,Cmax(0.324±0.126)mg/L,T1/2β(18.150±10.557)h,MRT(5.019±1.591)h,AUClast(1.094±0.588)h·mg/L,Vd(395 321.202±236 694.989)mL/kg,CLB(14 340.535±3 560.508)kg·mL/h,Flast(16.589±11.495)%,F0~∞(18.236±8.114)%。结果表明,特比萘芬片剂在犬体内吸收迅速,保留时间更长,消除更为缓慢,有长效抑菌效果。
The pharmacokinetics and absolute bioavailability of terbinafine were investigated by a cross-over design following single intravenous(5 mg/kg)and oral(20 mg/kg)administration of the drug in eight healthy Beagle dogs.A two-week washout period was allowed between different treatments.The concentrations of terbinafine in plasma were determined by HPLC and the concentration-time data were analyzed with WinNonlin5.2 program.The main pharmacokinetic parameters after intravenous administration were as follows:Tmax(0.083±0.000)h,Cmax(3.334±0.185)mg/L,T1/2β(15.158±8.558)h,MRT(2.443±1.132)h,AUClast(1.803±0.374)h· mg/L,Vd(49 778.164±25 594.370)mL/kg,CLB(2 414.907±577.369)kg·mL/h.The main pharmacokinetic parameters after oral administration were as follows:Tmax(1.875±0.791)h,Cmax(0.324±0.126)mg/L,T1/2β(18.150±10.557)h,MRT(5.019±1.591)h,AUClast(1.094±0.588)h·mg/L,Vd(395 321.202±236 694.989)mL/kg,CLB(14 340.535±3 560.508)kg·mL/h,Flast(16.589±11.495)%,F0~∞(18.236±8.114)%.The results demonstrated that terbinafine hydrochloride tablets was absorbed quickly and eliminated slowly.Also terbinafine hydrochloride tablets had a long retention time and a long-lasting antifungal effect.
The pharmacokinetics and absolute bioavailability of terbinafine were investigated by a cross-over design following single intravenous(5 mg/kg)and oral(20 mg/kg)administration of the drug in eight healthy Beagle dogs.A two-week washout period was allowed between different treatments.The concentrations of terbinafine in plasma were determined by HPLC and the concentration-time data were analyzed with WinNonlin5.2 program.The main pharmacokinetic parameters after intravenous administration were as follows:Tmax(0.083±0.000)h,Cmax(3.334±0.185)mg/L,T1/2β(15.158±8.558)h,MRT(2.443±1.132)h,AUClast(1.803±0.374)h· mg/L,Vd(49 778.164±25 594.370)mL/kg,CLB(2 414.907±577.369)kg·mL/h.The main pharmacokinetic parameters after oral administration were as follows:Tmax(1.875±0.791)h,Cmax(0.324±0.126)mg/L,T1/2β(18.150±10.557)h,MRT(5.019±1.591)h,AUClast(1.094±0.588)h·mg/L,Vd(395 321.202±236 694.989)mL/kg,CLB(14 340.535±3 560.508)kg·mL/h,Flast(16.589±11.495)%,F0~∞(18.236±8.114)%.The results demonstrated that terbinafine hydrochloride tablets was absorbed quickly and eliminated slowly.Also terbinafine hydrochloride tablets had a long retention time and a long-lasting antifungal effect.
引文
[1]邢文善,路芳,王秋香.盐酸特比萘芬药物制剂的研究进展[J].中国药房,2016(4):553-555.
[2]FELIX F S,FERREIRA L M C,ROSSINI P D O,et al.Quantification of terbinafine in pharmaceutical tablets using capillary electrophoresis with contactless conductivity detection and batch injection analysis with amperometric detection[J].Talanta,2012,101(22):220-225.
[3]丁莉坤,杨静,陈苏宁,等.LC-MS/MS法测定人血浆中特比萘芬浓度及其生物等效性评价[J].中国药师,2012(8):1118-1121.
[4]王灵杰,王娜,田媛,等.盐酸特比萘芬片人体药动学和生物等效性研究[J].中国现代应用药学,2008(3):217-220.
[5]陈红,孙艳伏,蔡丽伟,等.盐酸特比萘芬片在健康人体中的相对生物利用度及生物等效性试验[J].中国新药杂志,2012(9):1145.
[6]欧阳冬生,史卉妍,谭志荣,等.盐酸特比萘芬片的人体生物等效性研究[J].中国新药杂志,2008,14:1261-1263.
[7]吴云飞.盐酸特比萘芬的安全性和抗真菌药物的敏感性及临床疗效试验[D].江苏南京:南京农业大学,2012.
[8]谈鑫,潘炜华,邓淑文,等.国产盐酸特比萘芬对皮肤癣菌的体外抗菌活性研究[J].中国真菌学杂志,2015(1):22-24,29.
[9]汤伍辉.盐酸特比萘芬与伊曲康唑用于治疗真菌性皮肤病患者临床疗效的比较[J].抗感染药学,2015(6):965-967.
[10]乔瑞景.杀虫去癣汤联合盐酸特比萘芬乳膏治疗体股癣患者的临床效果[J].中国药物经济学,2016(1):90-91.
[11]高彤,姜辉,孙冬梅,等.评价盐酸特比萘芬片治疗真菌性皮肤病的临床疗效[J].中国医药指南,2014,18(1):180-181.
[12]刘伟.盐酸特比萘芬片治疗真菌性皮肤病的临床分析及安全性观察[J].中外医疗,2014,19:123-124.
[13]邢文善,路芳,王秋香.盐酸特比萘芬药物制剂的研究进展[J].中国药房,2016(4):553-555.
[14]倪睿,马晋隆,孙有丽,等.盐酸特比萘芬生物黏附性成膜凝胶的制备及其体外评价[J].中国药科大学学报,2015(6):671-676.
[15]何一鸣,张蜀,邓红,等.盐酸特比萘芬乳膏的释放度考察[J].中国新药杂志,2015(4):462-465,469.
[16]陈景勇,刘瑛,黄劲松,等.复方盐酸特比萘芬贴剂的制备与体外透皮性能研究[J].广东药学院学报,2015(3):296-299.
[17]杨柳,董博宇,白洁,等.犬用盐酸特比萘芬片剂矫味处方及含量测定研究[J].中国兽药杂志,2015(11):45-48.
[18]张洛,陈新,刘利锋,等.犬口服盐酸特比萘芬片的生物利用度研究[J].江苏农业科学,2011(5):306-308.
[19]何文跃,徐爱仁,陈武,等.反相高效液相色谱法检测人血浆特比萘芬浓度[J].中国药师,2012(9):1276-1278.
[20]李博,步芬,陈沄,等.LC-MS/MS法测定健康人血浆中的特比萘芬[J].药学与临床研究,2011(6):504-507.
[21]龚志成.人血浆中特比萘芬的HPLC测定及药动学[J].中国医药工业杂志,2008(8):603-605.
[22]王昂,丁焕中,高艳,等.盐酸特比萘芬胶囊在比格犬体内的药物动力学及生物利用度研究[J].华南农业大学学报,2012(4):556-560.
[23]NEWLAND J G,ABDELRAHMAN S M.Update on terbinafine with a focus on der matophytoses[J].Clin Cosmet Invest Dermatol,2009,2(2):49-63.
[24]TOUTAIN P L,CASTILLO J R E D,BOUSQUET-MLOU A.The pharmacokinetic-pharmacodynamic approach to a rational dosage regimen for antibiotics[J].Res Vet Sci,2002,73(2):105-114.
[25]参都哈西,古丽扎提,佐丽菲亚,等.犬皮肤真菌病的诊疗[J].现代农业科技,2011(7):348-349.
[25]CLAYTON Y M.Relevance of broad-spectrum and fungicidal activity of antifungals in the treatment of dermatomycoses[J].Br J Dermatol,1994,130(Supplement s43):7-8.
[26]FORREST A,NIX D E,BALLOW C H,et al.Pharmacodynamics ofⅣciprofloxacin in seriously ill patients[J].Antimicrob Agents Chemotherapy,1993,37:1073-1081.
[27]DUDLEY M N.Pharmacodynamics and pharmacokinetics of antibiotics with special reference to the fluoroquinolones[J].Am J Med,1991,91(6):45-50.
[2]FELIX F S,FERREIRA L M C,ROSSINI P D O,et al.Quantification of terbinafine in pharmaceutical tablets using capillary electrophoresis with contactless conductivity detection and batch injection analysis with amperometric detection[J].Talanta,2012,101(22):220-225.
[3]丁莉坤,杨静,陈苏宁,等.LC-MS/MS法测定人血浆中特比萘芬浓度及其生物等效性评价[J].中国药师,2012(8):1118-1121.
[4]王灵杰,王娜,田媛,等.盐酸特比萘芬片人体药动学和生物等效性研究[J].中国现代应用药学,2008(3):217-220.
[5]陈红,孙艳伏,蔡丽伟,等.盐酸特比萘芬片在健康人体中的相对生物利用度及生物等效性试验[J].中国新药杂志,2012(9):1145.
[6]欧阳冬生,史卉妍,谭志荣,等.盐酸特比萘芬片的人体生物等效性研究[J].中国新药杂志,2008,14:1261-1263.
[7]吴云飞.盐酸特比萘芬的安全性和抗真菌药物的敏感性及临床疗效试验[D].江苏南京:南京农业大学,2012.
[8]谈鑫,潘炜华,邓淑文,等.国产盐酸特比萘芬对皮肤癣菌的体外抗菌活性研究[J].中国真菌学杂志,2015(1):22-24,29.
[9]汤伍辉.盐酸特比萘芬与伊曲康唑用于治疗真菌性皮肤病患者临床疗效的比较[J].抗感染药学,2015(6):965-967.
[10]乔瑞景.杀虫去癣汤联合盐酸特比萘芬乳膏治疗体股癣患者的临床效果[J].中国药物经济学,2016(1):90-91.
[11]高彤,姜辉,孙冬梅,等.评价盐酸特比萘芬片治疗真菌性皮肤病的临床疗效[J].中国医药指南,2014,18(1):180-181.
[12]刘伟.盐酸特比萘芬片治疗真菌性皮肤病的临床分析及安全性观察[J].中外医疗,2014,19:123-124.
[13]邢文善,路芳,王秋香.盐酸特比萘芬药物制剂的研究进展[J].中国药房,2016(4):553-555.
[14]倪睿,马晋隆,孙有丽,等.盐酸特比萘芬生物黏附性成膜凝胶的制备及其体外评价[J].中国药科大学学报,2015(6):671-676.
[15]何一鸣,张蜀,邓红,等.盐酸特比萘芬乳膏的释放度考察[J].中国新药杂志,2015(4):462-465,469.
[16]陈景勇,刘瑛,黄劲松,等.复方盐酸特比萘芬贴剂的制备与体外透皮性能研究[J].广东药学院学报,2015(3):296-299.
[17]杨柳,董博宇,白洁,等.犬用盐酸特比萘芬片剂矫味处方及含量测定研究[J].中国兽药杂志,2015(11):45-48.
[18]张洛,陈新,刘利锋,等.犬口服盐酸特比萘芬片的生物利用度研究[J].江苏农业科学,2011(5):306-308.
[19]何文跃,徐爱仁,陈武,等.反相高效液相色谱法检测人血浆特比萘芬浓度[J].中国药师,2012(9):1276-1278.
[20]李博,步芬,陈沄,等.LC-MS/MS法测定健康人血浆中的特比萘芬[J].药学与临床研究,2011(6):504-507.
[21]龚志成.人血浆中特比萘芬的HPLC测定及药动学[J].中国医药工业杂志,2008(8):603-605.
[22]王昂,丁焕中,高艳,等.盐酸特比萘芬胶囊在比格犬体内的药物动力学及生物利用度研究[J].华南农业大学学报,2012(4):556-560.
[23]NEWLAND J G,ABDELRAHMAN S M.Update on terbinafine with a focus on der matophytoses[J].Clin Cosmet Invest Dermatol,2009,2(2):49-63.
[24]TOUTAIN P L,CASTILLO J R E D,BOUSQUET-MLOU A.The pharmacokinetic-pharmacodynamic approach to a rational dosage regimen for antibiotics[J].Res Vet Sci,2002,73(2):105-114.
[25]参都哈西,古丽扎提,佐丽菲亚,等.犬皮肤真菌病的诊疗[J].现代农业科技,2011(7):348-349.
[25]CLAYTON Y M.Relevance of broad-spectrum and fungicidal activity of antifungals in the treatment of dermatomycoses[J].Br J Dermatol,1994,130(Supplement s43):7-8.
[26]FORREST A,NIX D E,BALLOW C H,et al.Pharmacodynamics ofⅣciprofloxacin in seriously ill patients[J].Antimicrob Agents Chemotherapy,1993,37:1073-1081.
[27]DUDLEY M N.Pharmacodynamics and pharmacokinetics of antibiotics with special reference to the fluoroquinolones[J].Am J Med,1991,91(6):45-50.