外源化合物在鱼体内生物半减期的QSAR模型
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摘要
生物半减期(t1/2)是评价外源化合物在鱼体内蓄积效应的重要参数。实验测定t_(1/2)的速度慢、成本高,难以满足化学品生态风险评价的需求,需要发展替代实验的模型预测方法。本研究搜集了653种化合物t1/2实测值,采用多元线性回归(MLR)和支持向量机(SVM) 2种方法,建立了鱼体logt1/2的定量构效关系(QSAR)预测模型。MLR模型的校正决定系数(R(adj)~2)为0.751,均方根误差(RMSE_(train))为0.587,去一法交叉验证系数(Q_(LOO)~2)为0.735,外部验证系数(Q_(ext)~2)为0.682,这表明模型具有较好的拟合度、稳健性和预测能力。SVM模型具有更好的拟合和预测能力(R_(adj)~2=0.839,RMSE_(train)=0.457,Q_(ext)~2=0.708)。采用Williams法对模型的应用域进行表征。所建模型可用于预测多环芳烃、多氯联苯、多溴联苯醚、有机磷农药、药物等典型化合物,以及其他烷烃、环烷烃、烯烃、醇、醚、酸、酯、酮、含卤素化合物、芳香族化合物、含硫、氮、磷化合物的在鱼体内的logt1/2值。
Biological half-life(t_(1/2)) of chemicals is a key parameter for assessing bioaccumulation of xenobiotics.As the number of synthetic chemicals is huge,it is not practical to experimentally measure their t_(1/2) values one by one. It is important to develop alternative methods to predict the t_(1/2) values of xenobiotics. In this study,t_(1/2) values of 653 chemicals in fish were collected,and multiple linear regression(MLR) and support vector machine( SVM)methods were adopted to develop quantitative structure-activity relationship(QSAR) models for predicting t_(1/2). For the MLR model,the adjusted determination coefficient(R_(adj)~2) is 0.751,the root-mean-square error( RMSE) is 0.587,leave-one-out cross validated coefficient(Q_(LOO)~2) is 0.735 and external explained variance(Q_(ext)~2) is 0.682,which indicate that the MLR model has high goodness of fit,robustness,and predictive ability. The results of the SVM model also show high goodness of fit and good predictive ability( R_(adj.train)~2= 0.839,RMSEtrain= 0.457,Q_(ext)~2=0.708). The model application domains were characterized by the Williams plot. The obtained models can be used to predict logt_(1/2) of chemicals including polycyclic aromatic hydrocarbons,polychlorinated biphenyls,poly brominated diphenyl ethers,pesticides,pharmaceuticals,alkanes,naphthenic hydrocarbons,alkenes,alcohols,ethers,acids,esters,ketones,halogenated compounds,aromatics,organosulfur compounds,organonitrogen compounds and organophosphorus compounds.
Biological half-life(t_(1/2)) of chemicals is a key parameter for assessing bioaccumulation of xenobiotics.As the number of synthetic chemicals is huge,it is not practical to experimentally measure their t_(1/2) values one by one. It is important to develop alternative methods to predict the t_(1/2) values of xenobiotics. In this study,t_(1/2) values of 653 chemicals in fish were collected,and multiple linear regression(MLR) and support vector machine( SVM)methods were adopted to develop quantitative structure-activity relationship(QSAR) models for predicting t_(1/2). For the MLR model,the adjusted determination coefficient(R_(adj)~2) is 0.751,the root-mean-square error( RMSE) is 0.587,leave-one-out cross validated coefficient(Q_(LOO)~2) is 0.735 and external explained variance(Q_(ext)~2) is 0.682,which indicate that the MLR model has high goodness of fit,robustness,and predictive ability. The results of the SVM model also show high goodness of fit and good predictive ability( R_(adj.train)~2= 0.839,RMSEtrain= 0.457,Q_(ext)~2=0.708). The model application domains were characterized by the Williams plot. The obtained models can be used to predict logt_(1/2) of chemicals including polycyclic aromatic hydrocarbons,polychlorinated biphenyls,poly brominated diphenyl ethers,pesticides,pharmaceuticals,alkanes,naphthenic hydrocarbons,alkenes,alcohols,ethers,acids,esters,ketones,halogenated compounds,aromatics,organosulfur compounds,organonitrogen compounds and organophosphorus compounds.
引文
[1] Gobas F A,Wolf W D,Burkhard L P,et al. Revisiting bioaccumulation criteria for POPs and PBT assessments[J]. Integrated Environmental Assessment&Management,2010,5(4):624-637
[2] Burkhard L P,Arnot J A,Embry M R,et al. Comparing laboratory and field measured bioaccumulation endpoints[J]. Integrated Environmental Assessment&Management,2015,8(1):17-31
[3] Quintaneiro C,Patrício D,Novais S C,et al. Endocrine and physiological effects of linuron and S-metolachlor in zebrafish developing embryos[J]. Science of the Total Environment,2017,586:390-400
[4] Sogbanmu T O,Eszter N,Phillips D H,et al. Lagos lagoon sediment exogenous extracts and polycyclic aromatic hydrocarbons induce embryotoxic, teratogenic and genotoxic effects in Danio rerio(zebrafish)embryos[J]. Environmental Science and Pollution Research,2016,23(14):14489-14501
[5] Floehr T,Scholz-Starke B R,Xiao H,et al. Yangtze Three Gorges Reservoir,China:A holistic assessment of exogenous pollution,mutagenic effects of sediments and genotoxic impacts on fish[J]. Journal of Environmental Sciences,2015,38(12):63-82
[6] Papa E,Wal L V D,Arnot J A,et al. Metabolic biotransformation half-lives in fish:QSAR modeling and consensus analysis[J]. Science of the Total Environment,2014,470-471:1040-1046
[7] Klaschka U,Rother H A．‘Read this and be safe!’Comparison of regulatory processes for communicating risks of personal care products to European and South African consumers[J]. Environmental Sciences Europe,2013,25(1):30
[8] Bonsiewich M. News Briefs:EPA reports a decrease in toxic chemical emissions(U.S. Environmental Protection Agency)[J]. Civil Engineering,2006,5:41
[9] Wilhelm K P,Maibach H I. OECD guidelines for testing of chemicals[S]. Paris:OECD,2012
[10] Arnot J A,Mackay D,Parkerton T F,et al. A database of fish biotransformation rates for xenobiotics[J]. Environmental Toxicology&Chemistry,2008,27(11):2263-2270
[11] Burkhard L P. Factors influencing the design of bioaccumulation factor and biota-sediment accumulation factor field studies[J]. Environmental Toxicology&Chemistry,2010,22(2):351-360
[12] Nichols J W,Fitzsimmons P N,Burkhard L P. In vitroin vivo extrapolation of quantitative hepatic biotransformation data for fish. II. Modeled effects on chemical bioaccumulation[J]. Environmental Toxicology&Chemistry,2010,26(6):1304-1319
[13] Tunkel J,Mayo K,Austin C,et al. Practical considerations on the use of predictive models for regulatory purposes[J]. Environmental Science&Technology,2005,39(7):2188-2199
[14] Arnot J A,Meylan W,Tunkel J,et al. A quantitative structure-activity relationship for predicting metabolic biotransformation rates for xenobiotics in fish[J]. Environmental Toxicology&Chemistry,2009,28(6):1168-1177
[15] Brown T N,Arnot J A,Wania F. Iterative fragment selection:A group contribution approach to predicting fish biotransformation half-lives[J]. Environmental Science&Technology,2012,46(15):8253-8260
[16] Yang J,Li H,Ran Y,et al. Distribution and bioconcentration of endocrine disrupting chemicals in surface water and fish bile of the Pearl River Delta,South China[J]. Chemosphere,2014,107:439-446
[17] Liu J L,Wong M H. Pharmaceuticals and personal care products(PPCPs):A review on environmental contamination in China[J]. Environment International,2013,59(3):208-224
[18]王樱凝，崔迪，庞长泷，等．水中PPCPs的污染现状及其控制技术研究进展[J]．中国给水排水，2015,31(24):25-29Wang Y N,Cui D,Pang C L,et al. Pollution status and control technologies of pharmaceuticals and personal care products:Review[J]. China Water&Wastewater,2015,31(24):25-29(in Chinese)
[19]葛林科，张思玉，谢晴，等．抗生素在水环境中的光化学行为[J]．中国科学:化学，2010,40(2):124-135
[20]胡君剑，胡霞林，尹大强．药物与个人护理品在鱼体中的蓄积及代谢研究进展[J]．生态毒理学报，2015,10(2):89-99Hu J J,Hu X L,Yin D Q. The bioaccumulation and metabolism of pharmaceuticals and personal care products in fish[J]. Asian Journal of Ecotoxicology,2015,10(2):89-99(in Chinese)
[21] Wang D D,Feng L L,He G Y,et al. QSAR studies for assessing the acute toxicity of nitrobenzenes to Tetrahymena pyriformis[J]. Journal of the Serbian Chemical Society,2014,79(9):1111-1125
[22] Iman M,Davood A,Khamesipour A. Computational study of quinolone derivatives to improve their therapeutic index as anti-malaria agents:QSAR and QSTR[J]. Iranian Journal of Pharmaceutical Research,2015,14(3):775-784
[23] Vapnik V N. Statistical Learning Theory[M]. New York:John Wiley and Sons,1998
[24] Zhang W,Zhang Y. The relationship between model predictive ability and validated method in QSAR/QSPR study[J]. Computers&Applied Chemistry,2010,27(2):201-205
[25] Yao X J,Panaye A,Doucet J P,et al. Comparative study of QSAR/QSPR correlations using support vector machines,radial basis function neural networks,and multiple linear regression[J]. Journal of Chemical Information&Computer Sciences,2004,44(4):1257-1266
[26] Liu H X,Xue C X,Zhang R S,et al. Quantitative prediction of logk of peptides in high-performance liquid chromatography based on molecular descriptors by using the heuristic method and support vector machine[J].Journal of Chemical Information&Computerences,2005,44(6):1979-1986
[27] Doucet J P,Barbault F,Xia H,et al. Nonlinear SVM approaches to QSPR/QSAR studies and drug design[J]. Current Computer-Aided Drug Design,2007,3(4):263-289
[28] Wang J,Gardinali P R. Uptake and depuration of pharmaceuticals in reclaimed water by mosquito fish(Gambusia holbrooki):A worst-case,multiple-exposure scenario[J]. Environmental Toxicology&Chemistry,2013,32(8):1752-1758
[29] Ueno R. Metabolism and Pharmacokinetics of Sulfamonomethoxine in Edible Fish Species[M]//Xenobiotics in Fish. New York:Springer US,1999:201-212
[30] Newby N C,Mendona P C,Gamperl K,et al. Pharmacokinetics of morphine in fish:Winter flounder(Pseudopleuronectes americanus)and seawater-acclimated rainbow trout(Oncorhynchus mykiss)[J]. Comparative Biochemistry&Physiology Part C:Toxicology&Pharmacology,2006,143(3):275-283
[31] Tyrpenou A E,Kotzamanis Y P,Alexis M N. Flumequine depletion from muscle plus skin tissue of gilthead seabream(Sparus aurata L.)fed flumequine medicated feed in seawater at 18 and 24℃[J]. Aquaculture,2003,220(1-4):633-642
[32] Rigos G,Nengas I,Alexis M,et al. Tissue distribution and residue depletion of oxolinic acid in gilthead sea bream(Sparus aurata)and sharpsnout sea bream(Diplodus puntazzo)following multiple in-feed dosing[J].Aquaculture,2003,224(1):245-256
[33] Tyrpenou A E,Iossifidou E G,Psomas I E,et al. Tissue distribution and depletion of sarafloxacin hydrochloride after in feed administration in gilthead seabream(Sparus aurata L.)[J]. Aquaculture,2003,215(1-4):291-300
[34] Rogstad A,Hormazabal V,Ellingsen O F,et al. Pharmacokinetic study of oxytetracycline in fish. I. Absorption,distribution and accumulation in rainbow trout in freshwater[J]. Aquaculture,1991,96(3-4):219-226
[35] Liu W,Xu J,Zhou Y,et al. Pharmacokinetics and tissue residues of moroxydine hydrochloride in gibel carp,Carassius gibelio after oral administration[J]. Journal of Veterinary Pharmacology&Therapeutics,2016,39(4):398-404
[36] Liu H,Xue M,Wang J,et al. Tissue deposition and residue depletion in rainbow trout following continuous voluntary feeding with various levels of melamine or a blend of melamine and cyanuric acid[J]. Comparative Biochemistry&Physiology Part C:Toxicology&Pharmacology,2014,166(11):51-58
[37] Sun M,Li J,Gai C L,et al. Pharmacokinetics of difloxacin in olive flounder Paralichthys olivaceus at two water temperatures[J]. Journal of Veterinary Pharmacology&Therapeutics,2014,37(2):186-191
[38]李改娟，刘艳辉，祖岫杰，等．不同给药方式下培氟沙星在鲤体内的药代动力学研究[J]．大连海洋大学学报，2014,29(4):386-390Li G J,Liu Y H,Zu X J,et al. Pharmacokinetics of pefloxacin in common carp challenged by a single intramuscular injection and oral administration[J]. Journal of Dalian Ocean University,2014,29(4):386-390(in Chinese)
[39] Shan Q,Zhu X,Liu S,et al. Pharmacokinetics of cefquinome in tilapia(Oreochromis niloticus)after a single intramuscular or intraperitoneal administration[J]. Journal of Veterinary Pharmacology&Therapeutics,2015,38(6):601-605
[40] Yang F,Li Z L,Shan Q,et al. Pharmacokinetics of doxycycline in tilapia(Oreochromis aureus×Oreochromis niloticus)after intravenous and oral administration[J]. Journal of Veterinary Pharmacology&Therapeutics,2014,37(4):388-393
[41] Wang W,Luo L,Xiao H,et al. A pharmacokinetic and residual study of sulfadiazine/trimethoprim in mandarin fish(Siniperca chuatsi)with single-and multiple-dose oral administrations[J]. Journal of Veterinary Pharmacology&Therapeutics,2016,39(3):309-314
[42] Xu N,Gong B,Dong J,et al. Single intravascular and oral dose pharmacokinetics of mebendazole in blunt snout bream,Megalobrama amblycephala[J]. Journal of the World Aquaculture Society,2016,47(5):685-690
[43] Gore S R,Harms C A,Kukanich B,et al. Enrofloxacin pharmacokinetics in the European cuttlefish,Sepia officinalis,after a single i.v. injection and bath administration[J]. Journal of Veterinary Pharmacology&Therapeutics,2005,28(5):433-439
[44] Angélique L,Marielle T,Damien B,et al. Accumulation and half-lives of 13 pesticides in muscle tissue of freshwater fishes through food exposure[J]. Chemosphere,2013,91(4):530-535
[45] Feng J B,Huang D R,Zhong M,et al. Pharmacokinetics of florfenicol and behaviour of its metabolite florfenicol amine in orange-spotted grouper(Epinephelus coioides)after oral administration[J]. Journal of Fish Diseases,2016,39(7):833-843
[46] Tanoue R,Nomiyama K,Nakamura H,et al. Uptake and tissue distribution of pharmaceuticals and personal care products in wild fish from treated-wastewater-impacted streams[J]. Environmental Science&Technology,2015,49(19):11649-11658
[47] Frisch M J,Trucks G W,Sehlegel H B,et a1. Gaussian 09,revision a. 02[CP]. Wallingford,CT:Gaussian,Inc.,2009
[48] Hay P J. Ab initio effective core potentials for molecular calculations. Potentials for K to Au including the outermost core orbitals[J]. Journal of Chemical Physics,1985,82(1):299-310
[49] Tatete S R L. DRAGON(Software for Molecular Descriptor Calculation)Version 6. 0-2012[CP/OL].[2018-03-11]. http://www.talete.mi.it/
[50] Qin H,Chen J W,Wang Y,et al. Development and assessment of quantitative structure-activity relationship models for bioconcentration factors of exogenous pollutants[J]. Chinese Science Bulletin,2009,54(4):628-634
[2] Burkhard L P,Arnot J A,Embry M R,et al. Comparing laboratory and field measured bioaccumulation endpoints[J]. Integrated Environmental Assessment&Management,2015,8(1):17-31
[3] Quintaneiro C,Patrício D,Novais S C,et al. Endocrine and physiological effects of linuron and S-metolachlor in zebrafish developing embryos[J]. Science of the Total Environment,2017,586:390-400
[4] Sogbanmu T O,Eszter N,Phillips D H,et al. Lagos lagoon sediment exogenous extracts and polycyclic aromatic hydrocarbons induce embryotoxic, teratogenic and genotoxic effects in Danio rerio(zebrafish)embryos[J]. Environmental Science and Pollution Research,2016,23(14):14489-14501
[5] Floehr T,Scholz-Starke B R,Xiao H,et al. Yangtze Three Gorges Reservoir,China:A holistic assessment of exogenous pollution,mutagenic effects of sediments and genotoxic impacts on fish[J]. Journal of Environmental Sciences,2015,38(12):63-82
[6] Papa E,Wal L V D,Arnot J A,et al. Metabolic biotransformation half-lives in fish:QSAR modeling and consensus analysis[J]. Science of the Total Environment,2014,470-471:1040-1046
[7] Klaschka U,Rother H A．‘Read this and be safe!’Comparison of regulatory processes for communicating risks of personal care products to European and South African consumers[J]. Environmental Sciences Europe,2013,25(1):30
[8] Bonsiewich M. News Briefs:EPA reports a decrease in toxic chemical emissions(U.S. Environmental Protection Agency)[J]. Civil Engineering,2006,5:41
[9] Wilhelm K P,Maibach H I. OECD guidelines for testing of chemicals[S]. Paris:OECD,2012
[10] Arnot J A,Mackay D,Parkerton T F,et al. A database of fish biotransformation rates for xenobiotics[J]. Environmental Toxicology&Chemistry,2008,27(11):2263-2270
[11] Burkhard L P. Factors influencing the design of bioaccumulation factor and biota-sediment accumulation factor field studies[J]. Environmental Toxicology&Chemistry,2010,22(2):351-360
[12] Nichols J W,Fitzsimmons P N,Burkhard L P. In vitroin vivo extrapolation of quantitative hepatic biotransformation data for fish. II. Modeled effects on chemical bioaccumulation[J]. Environmental Toxicology&Chemistry,2010,26(6):1304-1319
[13] Tunkel J,Mayo K,Austin C,et al. Practical considerations on the use of predictive models for regulatory purposes[J]. Environmental Science&Technology,2005,39(7):2188-2199
[14] Arnot J A,Meylan W,Tunkel J,et al. A quantitative structure-activity relationship for predicting metabolic biotransformation rates for xenobiotics in fish[J]. Environmental Toxicology&Chemistry,2009,28(6):1168-1177
[15] Brown T N,Arnot J A,Wania F. Iterative fragment selection:A group contribution approach to predicting fish biotransformation half-lives[J]. Environmental Science&Technology,2012,46(15):8253-8260
[16] Yang J,Li H,Ran Y,et al. Distribution and bioconcentration of endocrine disrupting chemicals in surface water and fish bile of the Pearl River Delta,South China[J]. Chemosphere,2014,107:439-446
[17] Liu J L,Wong M H. Pharmaceuticals and personal care products(PPCPs):A review on environmental contamination in China[J]. Environment International,2013,59(3):208-224
[18]王樱凝，崔迪，庞长泷，等．水中PPCPs的污染现状及其控制技术研究进展[J]．中国给水排水，2015,31(24):25-29Wang Y N,Cui D,Pang C L,et al. Pollution status and control technologies of pharmaceuticals and personal care products:Review[J]. China Water&Wastewater,2015,31(24):25-29(in Chinese)
[19]葛林科，张思玉，谢晴，等．抗生素在水环境中的光化学行为[J]．中国科学:化学，2010,40(2):124-135
[20]胡君剑，胡霞林，尹大强．药物与个人护理品在鱼体中的蓄积及代谢研究进展[J]．生态毒理学报，2015,10(2):89-99Hu J J,Hu X L,Yin D Q. The bioaccumulation and metabolism of pharmaceuticals and personal care products in fish[J]. Asian Journal of Ecotoxicology,2015,10(2):89-99(in Chinese)
[21] Wang D D,Feng L L,He G Y,et al. QSAR studies for assessing the acute toxicity of nitrobenzenes to Tetrahymena pyriformis[J]. Journal of the Serbian Chemical Society,2014,79(9):1111-1125
[22] Iman M,Davood A,Khamesipour A. Computational study of quinolone derivatives to improve their therapeutic index as anti-malaria agents:QSAR and QSTR[J]. Iranian Journal of Pharmaceutical Research,2015,14(3):775-784
[23] Vapnik V N. Statistical Learning Theory[M]. New York:John Wiley and Sons,1998
[24] Zhang W,Zhang Y. The relationship between model predictive ability and validated method in QSAR/QSPR study[J]. Computers&Applied Chemistry,2010,27(2):201-205
[25] Yao X J,Panaye A,Doucet J P,et al. Comparative study of QSAR/QSPR correlations using support vector machines,radial basis function neural networks,and multiple linear regression[J]. Journal of Chemical Information&Computer Sciences,2004,44(4):1257-1266
[26] Liu H X,Xue C X,Zhang R S,et al. Quantitative prediction of logk of peptides in high-performance liquid chromatography based on molecular descriptors by using the heuristic method and support vector machine[J].Journal of Chemical Information&Computerences,2005,44(6):1979-1986
[27] Doucet J P,Barbault F,Xia H,et al. Nonlinear SVM approaches to QSPR/QSAR studies and drug design[J]. Current Computer-Aided Drug Design,2007,3(4):263-289
[28] Wang J,Gardinali P R. Uptake and depuration of pharmaceuticals in reclaimed water by mosquito fish(Gambusia holbrooki):A worst-case,multiple-exposure scenario[J]. Environmental Toxicology&Chemistry,2013,32(8):1752-1758
[29] Ueno R. Metabolism and Pharmacokinetics of Sulfamonomethoxine in Edible Fish Species[M]//Xenobiotics in Fish. New York:Springer US,1999:201-212
[30] Newby N C,Mendona P C,Gamperl K,et al. Pharmacokinetics of morphine in fish:Winter flounder(Pseudopleuronectes americanus)and seawater-acclimated rainbow trout(Oncorhynchus mykiss)[J]. Comparative Biochemistry&Physiology Part C:Toxicology&Pharmacology,2006,143(3):275-283
[31] Tyrpenou A E,Kotzamanis Y P,Alexis M N. Flumequine depletion from muscle plus skin tissue of gilthead seabream(Sparus aurata L.)fed flumequine medicated feed in seawater at 18 and 24℃[J]. Aquaculture,2003,220(1-4):633-642
[32] Rigos G,Nengas I,Alexis M,et al. Tissue distribution and residue depletion of oxolinic acid in gilthead sea bream(Sparus aurata)and sharpsnout sea bream(Diplodus puntazzo)following multiple in-feed dosing[J].Aquaculture,2003,224(1):245-256
[33] Tyrpenou A E,Iossifidou E G,Psomas I E,et al. Tissue distribution and depletion of sarafloxacin hydrochloride after in feed administration in gilthead seabream(Sparus aurata L.)[J]. Aquaculture,2003,215(1-4):291-300
[34] Rogstad A,Hormazabal V,Ellingsen O F,et al. Pharmacokinetic study of oxytetracycline in fish. I. Absorption,distribution and accumulation in rainbow trout in freshwater[J]. Aquaculture,1991,96(3-4):219-226
[35] Liu W,Xu J,Zhou Y,et al. Pharmacokinetics and tissue residues of moroxydine hydrochloride in gibel carp,Carassius gibelio after oral administration[J]. Journal of Veterinary Pharmacology&Therapeutics,2016,39(4):398-404
[36] Liu H,Xue M,Wang J,et al. Tissue deposition and residue depletion in rainbow trout following continuous voluntary feeding with various levels of melamine or a blend of melamine and cyanuric acid[J]. Comparative Biochemistry&Physiology Part C:Toxicology&Pharmacology,2014,166(11):51-58
[37] Sun M,Li J,Gai C L,et al. Pharmacokinetics of difloxacin in olive flounder Paralichthys olivaceus at two water temperatures[J]. Journal of Veterinary Pharmacology&Therapeutics,2014,37(2):186-191
[38]李改娟，刘艳辉，祖岫杰，等．不同给药方式下培氟沙星在鲤体内的药代动力学研究[J]．大连海洋大学学报，2014,29(4):386-390Li G J,Liu Y H,Zu X J,et al. Pharmacokinetics of pefloxacin in common carp challenged by a single intramuscular injection and oral administration[J]. Journal of Dalian Ocean University,2014,29(4):386-390(in Chinese)
[39] Shan Q,Zhu X,Liu S,et al. Pharmacokinetics of cefquinome in tilapia(Oreochromis niloticus)after a single intramuscular or intraperitoneal administration[J]. Journal of Veterinary Pharmacology&Therapeutics,2015,38(6):601-605
[40] Yang F,Li Z L,Shan Q,et al. Pharmacokinetics of doxycycline in tilapia(Oreochromis aureus×Oreochromis niloticus)after intravenous and oral administration[J]. Journal of Veterinary Pharmacology&Therapeutics,2014,37(4):388-393
[41] Wang W,Luo L,Xiao H,et al. A pharmacokinetic and residual study of sulfadiazine/trimethoprim in mandarin fish(Siniperca chuatsi)with single-and multiple-dose oral administrations[J]. Journal of Veterinary Pharmacology&Therapeutics,2016,39(3):309-314
[42] Xu N,Gong B,Dong J,et al. Single intravascular and oral dose pharmacokinetics of mebendazole in blunt snout bream,Megalobrama amblycephala[J]. Journal of the World Aquaculture Society,2016,47(5):685-690
[43] Gore S R,Harms C A,Kukanich B,et al. Enrofloxacin pharmacokinetics in the European cuttlefish,Sepia officinalis,after a single i.v. injection and bath administration[J]. Journal of Veterinary Pharmacology&Therapeutics,2005,28(5):433-439
[44] Angélique L,Marielle T,Damien B,et al. Accumulation and half-lives of 13 pesticides in muscle tissue of freshwater fishes through food exposure[J]. Chemosphere,2013,91(4):530-535
[45] Feng J B,Huang D R,Zhong M,et al. Pharmacokinetics of florfenicol and behaviour of its metabolite florfenicol amine in orange-spotted grouper(Epinephelus coioides)after oral administration[J]. Journal of Fish Diseases,2016,39(7):833-843
[46] Tanoue R,Nomiyama K,Nakamura H,et al. Uptake and tissue distribution of pharmaceuticals and personal care products in wild fish from treated-wastewater-impacted streams[J]. Environmental Science&Technology,2015,49(19):11649-11658
[47] Frisch M J,Trucks G W,Sehlegel H B,et a1. Gaussian 09,revision a. 02[CP]. Wallingford,CT:Gaussian,Inc.,2009
[48] Hay P J. Ab initio effective core potentials for molecular calculations. Potentials for K to Au including the outermost core orbitals[J]. Journal of Chemical Physics,1985,82(1):299-310
[49] Tatete S R L. DRAGON(Software for Molecular Descriptor Calculation)Version 6. 0-2012[CP/OL].[2018-03-11]. http://www.talete.mi.it/
[50] Qin H,Chen J W,Wang Y,et al. Development and assessment of quantitative structure-activity relationship models for bioconcentration factors of exogenous pollutants[J]. Chinese Science Bulletin,2009,54(4):628-634