Tissue-specific uptake of the benzodiazepine oxazepam in adult Eurasian perch (Perca fluviatilis)
Martina Heynen A B C , Tomas Brodin A , Jonatan Klaminder A , Micael Jonsson A and Jerker Fick B
+ Author Affiliations
- Author Affiliations
A Department of Ecology and Environmental Science, Linnaeus väg 6, 901 87 Umeå, Umeå University, Sweden.
B Department of Chemistry, Linnaeus väg 10, 901 87 Umeå, Umeå University, Sweden.
C Corresponding author. Email: martina_heynen@web.de
Environmental Chemistry 13(5) 849-853 https://doi.org/10.1071/EN16027
Submitted: 5 February 2016 Accepted: 26 April 2016 Published: 31 May 2016
Environmental context. Although pharmaceuticals are found in wild fish, there is no consensus as to which fish tissue to use when measuring the pharmaceutical concentrations. Using the psychiatric pharmaceutical oxazepam in Eurasian perch as an example, we found that oxazepam was distributed in the perch tissues in the following order of concentration: muscle < liver = brain < blood plasma. These results help to interpret and compare previous studies, and provide guidance for future studies.
Abstract. Psychoactive substances are used worldwide and constitute one of the common groups of pharmaceutical contaminants in surface waters. Typically, in field surveys and laboratory studies, muscle or whole-body homogenates are used to quantify pharmaceutical concentrations in biota, although uptake of pharmaceuticals may be tissue-specific. Therefore, the aim of this study was to investigate the tissue-specific (muscle, liver, brain and blood plasma) uptake of the anxiolytic oxazepam in adult Eurasian perch (Perca fluviatilis). In laboratory experiments, perch were exposed to four different concentrations (2, 4, 12 and 20 µg L–1) of oxazepam for 6 days, and muscle, liver, brain tissue and blood plasma were sampled to determine tissue-specific bioconcentration. We found that the tissue-specific bioconcentration was independent of oxazepam concentration. However, among tissue types, bioconcentration was significantly different, with the concentration in muscle < liver = brain < blood plasma. Hence, it is important to consider the type of tissue used to quantify pharmaceutical uptake in fish, for predictions of species-specific sensitivity and comparisons across studies. Furthermore, our results indicate a somewhat lower transportability (brain/plasma ratio 0.54) of oxazepam from blood to brain in fish compared with in mammals, which should be kept in mind when employing ‘read-across’ approaches.
Additional keywords: blood concentration, brain concentration, distribution coefficient, pharmaceutical pollution, tissue-specific bioconcentration.
References
[1] V. Calisto, V. I. Esteves, Psychiatric pharmaceuticals in the environment. Chemosphere 2009, 77, 1257.| Psychiatric pharmaceuticals in the environment.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1MXhtlyrtb%2FP&md5=a3ff50c2d0c0c84823d30089979d60ccCAS | 19815251PubMed |
[2] V. Calisto, M. R. M. Domingues, V. I. Esteves, Photodegradation of psychiatric pharmaceuticals in aquatic environments – kinetics and photodegradation products. Water Res. 2011, 45, 6097.
| Photodegradation of psychiatric pharmaceuticals in aquatic environments – kinetics and photodegradation products.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3MXhtlWmurvJ&md5=7441606673fe43fc4ee54357ef73c09dCAS | 21943883PubMed |
[3] P. M. Bradley, L. B. Barber, J. W. Duris, W. T. Foreman, E. T. Furlong, L. E. Hubbard, K. J. Hutchinson, S. H. Keefe, D. W. Kolpin, Riverbank filtration potential of pharmaceuticals in a wastewater-impacted stream. Environ. Pollut. 2014, 193, 173.
| Riverbank filtration potential of pharmaceuticals in a wastewater-impacted stream.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC2cXht1ensbnK&md5=7c2fb9ac9e2b5935c7beb542c72c4c05CAS | 25038376PubMed |
[4] P. D. Scott, M. Bartkow, S. J. Blockwell, H. M. Coleman, S. J. Khan, R. Lim, J. A. McDonald, H. Nice, D. Nugegoda, V. Pettigrove, L. A. Tremblay, M. S. Warne, F. D. L. Leusch, A national survey of trace organic contaminants in Australian rivers. J. Environ. Qual. 2014, 43, 1702.
| A national survey of trace organic contaminants in Australian rivers.Crossref | GoogleScholarGoogle Scholar | 25603256PubMed |
[5] Z. Wang, X. H. Zhang, Y. Huang, H. Wang, Comprehensive evaluation of pharmaceuticals and personal care products (PPCPs) in typical highly urbanized regions across China. Environ. Pollut. 2015, 204, 223.
| Comprehensive evaluation of pharmaceuticals and personal care products (PPCPs) in typical highly urbanized regions across China.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC2MXntlWlsrw%3D&md5=7c1c64c71bacc346e190a90d9aae2c63CAS | 25982548PubMed |
[6] T. Brodin, S. Piovano, J. Fick, J. Klaminder, M. Heynen, M. Jonsson, Ecological effects of pharmaceuticals in aquatic systems – impacts through behavioural alterations. Phil. Trans. R. Soc. B. 2014, 369, 20130580.
| Ecological effects of pharmaceuticals in aquatic systems – impacts through behavioural alterations.Crossref | GoogleScholarGoogle Scholar | 25405968PubMed |
[7] B. W. Brooks, Fish on Prozac (and Zoloft): ten years later. Aquat. Toxicol. 2014, 151, 61.
| Fish on Prozac (and Zoloft): ten years later.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC2cXhvVWktr4%3D&md5=371c9f163e8e11f7f865186d68a2d7f2CAS | 24503458PubMed |
[8] P.-O. Montiglio, R. Royaute, Contaminants as a neglected source of behavioural variation. Anim. Behav. 2014, 88, 29.
| Contaminants as a neglected source of behavioural variation.Crossref | GoogleScholarGoogle Scholar |
[9] A. R. Brown, L. Gunnarsson, E. Kristiansson, C. R. Tyler, Assessing variation in the potential susceptibility of fish to pharmaceuticals, considering evolutionary differences in their physiology and ecology. Phil. Trans. R. Soc. B. 2014, 369, 20130576.
| Assessing variation in the potential susceptibility of fish to pharmaceuticals, considering evolutionary differences in their physiology and ecology.Crossref | GoogleScholarGoogle Scholar | 25405965PubMed |
[10] L. Gunnarsson, A. Jauhiainen, E. Kristiansson, O. Nerman, D. G. J. Larsson, Evolutionary conservation of human drug targets in organisms used for environmental risk assessments. Environ. Sci. Technol. 2008, 42, 5807.
| Evolutionary conservation of human drug targets in organisms used for environmental risk assessments.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1cXns1yqtrY%3D&md5=b9d1d08bbfb70859553e2c58653d3e4bCAS | 18754513PubMed |
[11] A. Brayfield, Martindale: The Complete Drug Reference, Electronic Version (Edn 38) (Pharmaceutical Press: London). Available at www.medicinescomplete.com [verified 5 May 2016].
[12] J. G. Langner, B. K. Gan, R. H. Liu, L. D. Baugh, P. Chand, J. L. Weng, C. Edwards, A. S. Walia, Enzymatic digestion, solid-phase extraction, and gas chromatography/mass spectrometry of derivatized intact oxazepam in urine. Clin. Chem. 1991, 37, 1595.
| 1:CAS:528:DyaK3MXlslequ7w%3D&md5=cdf1b98ca247303c11e35ce6b9608303CAS | 1893596PubMed |
[13] J. Klaminder, M. Jonsson, J. Fick, A. Sunderlin, T. Brodin, The conceptual imperfection of aquatic risk assessment tests: highlighting the need for tests designed to detect therapeutic effects of pharmaceutical contaminants. Environ. Res. Lett. 2014, 9, 084003.
| The conceptual imperfection of aquatic risk assessment tests: highlighting the need for tests designed to detect therapeutic effects of pharmaceutical contaminants.Crossref | GoogleScholarGoogle Scholar |
[14] T. Brodin, J. Fick, M. Jonsson, J. Klaminder, Dilute concentrations of a psychiatric drug alter behavior of fish from natural populations. Science 2013, 339, 814.
| Dilute concentrations of a psychiatric drug alter behavior of fish from natural populations.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3sXit1ygtLk%3D&md5=6fb6391c234d0633b27561a663b3807aCAS | 23413353PubMed |
[15] S. R. Hughes, P. Kay, L. E. Brown, Global synthesis and critical evaluation of pharmaceutical data sets collected from river systems. Environ. Sci. Technol. 2013, 47, 661.
| Global synthesis and critical evaluation of pharmaceutical data sets collected from river systems.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC38XhvVSntrnL&md5=cf3c704b65e189345099124d96d5a25eCAS | 23227929PubMed |
[16] A. Mendoza, J. L. Rodríguez-Gil, S. González-Alonso, N. Mastroianni, M. López de Alda, D. Barceló, Y. Valcárcel, Drugs of abuse and benzodiazepines in the Madrid Region (central Spain): seasonal variation in river waters, occurrence in tap water and potential environmental and human risk. Environ. Int. 2014, 70, 76.
| Drugs of abuse and benzodiazepines in the Madrid Region (central Spain): seasonal variation in river waters, occurrence in tap water and potential environmental and human risk.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC2cXhtFCitrvF&md5=df61b122226a6176401f40da6a44bfc9CAS | 24908641PubMed |
[17] R. Loos, R. Carvalho, D. C. António, S. Comero, G. Locoro, S. Tavazzi, B. Paracchini, M. Ghiani, T. Lettieri, L. Blaha, B. Jarosova, S. Voorspoels, K. Servaes, P. Haglund, J. Fick, R. H. Lindberg, D. Schwesig, B. M. Gawlik, EU-wide monitoring survey on emerging polar organic contaminants in wastewater treatment plant effluents. Water Res. 2013, 47, 6475.
| EU-wide monitoring survey on emerging polar organic contaminants in wastewater treatment plant effluents.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3sXhsFCjs7nE&md5=3453e5cde37088435a81c72cb7530e87CAS | 24091184PubMed |
[18] K. A. Maruya, D. E. Vidal-Dorsch, S. M. Bay, J. W. Kwon, K. Xia, K. L. Armbrust, Organic contaminants of emerging concern in sediments and flatfish collected near outfalls discharging treated wastewater effluent to the Southern California Bight. Environ. Toxicol. Chem. 2012, 31, 2683.
| Organic contaminants of emerging concern in sediments and flatfish collected near outfalls discharging treated wastewater effluent to the Southern California Bight.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC38XhslGgsrvO&md5=79b16da8627ca015e5c74b9f139f4d2eCAS | 22987513PubMed |
[19] A. Zenker, M. R. Cicero, F. Trestinaci, P. Bottoni, M. Carere, Bioaccumulation and biomagnification potential of pharmaceuticals with a focus to the aquatic environment. J. Environ. Manage. 2014, 133, 378.
| Bioaccumulation and biomagnification potential of pharmaceuticals with a focus to the aquatic environment.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC2cXhs1Cltb8%3D&md5=7fba4b980bbb117ac92fd818c52ef804CAS | 24419205PubMed |
[20] S. N. Garcia, M. Foster, L. A. Constantine, D. B. Huggett, Field and laboratory fish tissue accumulation of the anti-convulsant drug carbamazepine. Ecotoxicol. Environ. Saf. 2012, 84, 207.
| Field and laboratory fish tissue accumulation of the anti-convulsant drug carbamazepine.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC38XhtlSgsbvN&md5=ffc5cb2a177f6d0fb04ad3d8c534bc22CAS | 22902163PubMed |
[21] K. Grabicova, R. H. Lindberg, M. Östman, R. Grabic, T. Randak, D. G. Joakim Larsson, J. Fick, Tissue-specific bioconcentration of antidepressants in fish exposed to effluent from a municipal sewage treatment plant. Sci. Total Environ. 2014, 488–489, 46.
| Tissue-specific bioconcentration of antidepressants in fish exposed to effluent from a municipal sewage treatment plant.Crossref | GoogleScholarGoogle Scholar | 24814035PubMed |
[22] R. Tanoue, K. Nomiyama, H. Nakamura, T. Hayashi, J.-W. Kim, T. Isobe, R. Shinohara, S. Tanabe, Simultaneous determination of polar pharmaceuticals and personal care products in biological organs and tissues. J. Chromatogr. A 2014, 1355, 193.
| Simultaneous determination of polar pharmaceuticals and personal care products in biological organs and tissues.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC2cXhtVCjtb%2FL&md5=8586a8bffa5fc77d74fb7f2b34823e00CAS | 24958034PubMed |
[23] B. Huerta, S. Rodriguez-Mozaz, D. Barcelo, Pharmaceuticals in biota in the aquatic environment: analytical methods and environmental implications. Anal. Bioanal. Chem. 2012, 404, 2611.
| Pharmaceuticals in biota in the aquatic environment: analytical methods and environmental implications.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC38XotFygu7g%3D&md5=dcaf37e7ac2ae935b882a7f3c7e3faa2CAS | 22678760PubMed |
[24] M. M. Schultz, E. T. Furlong, D. W. Kolpin, S. L. Werner, H. L. Schoenfuss, L. B. Barber, V. S. Blazer, D. O. Norris, A. M. Vajda, Antidepressant pharmaceuticals in two US effluent-impacted streams: occurrence and fate in water and sediment, and selective uptake in fish neural tissue. Environ. Sci. Technol. 2010, 44, 1918.
| Antidepressant pharmaceuticals in two US effluent-impacted streams: occurrence and fate in water and sediment, and selective uptake in fish neural tissue.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3cXhtlWltLY%3D&md5=75e5d2b58b20cc1cb102c3fca3331904CAS | 20121081PubMed |
[25] J. Fick, R. H. Lindberg, J. Parkkonen, B. J. O. Arvidsson, M. Tysklind, D. G. J. Larsson, Therapeutic levels of levonorgestrel detected in blood plasma of fish: results from screening rainbow trout exposed to treated sewage effluents. Environ. Sci. Technol. 2010, 44, 2661.
| Therapeutic levels of levonorgestrel detected in blood plasma of fish: results from screening rainbow trout exposed to treated sewage effluents.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3cXjtVyit7o%3D&md5=521ef7a44a4dba01570f6beed8bda32fCAS | 20222725PubMed |
[26] D. B. Huggett, J. C. Cook, J. E. Ericson, R. T. A. Williams, A theoretical model for utilizing mammalian pharmacology and safety data to prioritize potential impacts of human pharmaceuticals to fish. Hum. Ecol. Risk. Assess 2003, 9, 1789.
| A theoretical model for utilizing mammalian pharmacology and safety data to prioritize potential impacts of human pharmaceuticals to fish.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2cXmt1Wqtg%3D%3D&md5=eefc936c3d06fbacc44282a34a84ca87CAS |
[27] M. Rand-Weaver, L. Margiotta-Casaluci, A. Patel, G. H. Panter, S. F. Owen, J. P. Sumpter, The read-across hypothesis and environmental risk assessment of pharmaceuticals. Environ. Sci. Technol. 2013, 47, 11384.
| The read-across hypothesis and environmental risk assessment of pharmaceuticals.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3sXhtlyqurjL&md5=240c8c94feca2a771d519aadcdfe30beCAS | 24006913PubMed |
[28] G. C. Nallani, R. E. Edziyie, P. M. Paulos, B. J. Venables, L. A. Constantine, D. B. Huggett, Bioconcentration of two basic pharmaceuticals, verapamil and clozapine, in fish. Environ. Toxicol. Chem. 2016, 35, 593.
| Bioconcentration of two basic pharmaceuticals, verapamil and clozapine, in fish.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC28XitFGgsbg%3D&md5=0b3400541ee5c7254147101ac1fde3bfCAS | 26753615PubMed |
[29] M. Kottelat, J. Freyhof, Handbook of European Freshwater Fishes 2007 (Kottelat, Cornol and Freyhof: Berlin).
[30] M. Heynen, J. Fick, M. Jonsson, J. Klaminder, T. Brodin, Effect of bioconcentration and trophic transfer on realized exposure to oxazepam in two predators, the dragonfly larvae (Aeshna grandis) and the Eurasian perch (Perca fluviatilis). Environ. Toxicol. Chem. 2016, 35, 930.
| Effect of bioconcentration and trophic transfer on realized exposure to oxazepam in two predators, the dragonfly larvae (Aeshna grandis) and the Eurasian perch (Perca fluviatilis).Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC28XivFyku7Y%3D&md5=cfa28bed6c1b964e501f8c5d3dd0c5b8CAS | 26762222PubMed |
[31] R Development Core Team, R: a language and environment for statistical computing, R version 3.0.2 [2013–09–25] 2014 (R Foundation for Statistical Computing: Vienna, Austria). www.R-project.org [verified 10 February 2014].
[32] B. W. Brooks, C. K. Chambliss, S. K. Stanley, A. Ramirez, K. E. Banks, R. D. Johnson, R. J. Lewis, Determination of select antidepressants in fish from an effluent-dominated stream. Environ. Toxicol. Chem. 2005, 24, 464.
| Determination of select antidepressants in fish from an effluent-dominated stream.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2MXivVGnt70%3D&md5=3edac20f34ad34c14846cac02dd33073CAS | 15720009PubMed |
[33] A. J. Ramirez, R. A. Brain, S. Usenko, M. O. Mottaleb, J. G. O’Donnell, L. L. Stahl, J. B. Wathen, B. D. Snyder, J. L. Pitt, P. Perez-Hurtado, L. L. Dobbins, B. W. Brooks, C. K. Chambliss, Occurrence of pharmaceuticals and personal care products in fish: results of a national pilot study in the United States. Environ. Toxicol. Chem. 2009, 28, 2587.
| Occurrence of pharmaceuticals and personal care products in fish: results of a national pilot study in the United States.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1MXhsV2lt7fO&md5=70104554582c8973882b4d2dcb077e2fCAS | 19320536PubMed |
[34] P. Verlicchi, M. Al Aukidy, E. Zambello, Occurrence of pharmaceutical compounds in urban wastewater: removal, mass load and environmental risk after a secondary treatment – a review. Sci. Total Environ. 2012, 429, 123.
| Occurrence of pharmaceutical compounds in urban wastewater: removal, mass load and environmental risk after a secondary treatment – a review.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC38Xos1Cntbo%3D&md5=7ba263e67b9f055e6bd9d942bcade00cCAS | 22583809PubMed |
[35] X. Tan, S.-Y. Yim, P. Uppu, K. M. Kleinow, Enhanced bioaccumulation of dietary contaminants in catfish with exposure to the waterborne surfactant linear alkylbenzene sulfonate. Aquat. Toxicol. 2010, 99, 300.
| Enhanced bioaccumulation of dietary contaminants in catfish with exposure to the waterborne surfactant linear alkylbenzene sulfonate.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3cXosV2jsbs%3D&md5=85d24e0594f5115839f76058ab5c1d26CAS | 20541817PubMed |
[36] T. Blewett, D. L. McLatchy, C. M. Wood, The effects of temperature and salinity on 17-α-ethynylestradiol uptake and its relationship to oxygen consumption in the model euryhaline teleost (Fundulus heteroclitus). Aquat. Toxicol. 2013, 127, 61.
| The effects of temperature and salinity on 17-α-ethynylestradiol uptake and its relationship to oxygen consumption in the model euryhaline teleost (Fundulus heteroclitus).Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3sXmvV2mtQ%3D%3D&md5=54978a5dcfa4df7323b0b4ec04d723b4CAS | 22575576PubMed |
[37] F. Orias, L. Simon, G. Mialdea, A. Clair, V. Brosselin, Y. Perrodin, Bioconcentration of 15N-tamoxifen at environmental concentration in liver, gonad and muscle of Danio rerio. Ecotoxicol. Environ. Saf. 2015, 120, 457.
| Bioconcentration of 15N-tamoxifen at environmental concentration in liver, gonad and muscle of Danio rerio.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC2MXht1KgtbzJ&md5=5989c3588c71db398f6da82f39ce7eb4CAS | 26163873PubMed |
[38] R. Tanoue, K. Nomiyama, H. Nakamura, J.-W. Kim, T. Isobe, R. Shinohara, T. Kunisue, S. Tanabe, Uptake and tissue distribution of pharmaceuticals and personal care products in wild fish from treated-wastewater-impacted streams. Environ. Sci. Technol. 2015, 49, 11649.
| Uptake and tissue distribution of pharmaceuticals and personal care products in wild fish from treated-wastewater-impacted streams.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC2MXhsVKlsr7N&md5=c022a24d09f862d44ac501d3360ece28CAS | 26348835PubMed |
[39] J. A. Arnot, F. A. P. C. Gobas, A review of bioconcentration factor (BCF) and bioaccumulation factor (BAF) assessments for organic chemicals in aquatic organisms. Environ. Rev. 2006, 14, 257.
| A review of bioconcentration factor (BCF) and bioaccumulation factor (BAF) assessments for organic chemicals in aquatic organisms.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2sXitFGktbk%3D&md5=67e3f8ed86bb11e450dd272d9846fa3cCAS |
[40] R. Namdari, S. Abedini, F. C. P. Law, A comparative tissue distribution study of oxytetracycline in rainbow trout, Oncorhynchus mykiss (Walbaum), and chinook salmon, Oncorhynchus tshawytscha (Walbaum). Aquacult. Res. 1999, 30, 279.
| A comparative tissue distribution study of oxytetracycline in rainbow trout, Oncorhynchus mykiss (Walbaum), and chinook salmon, Oncorhynchus tshawytscha (Walbaum).Crossref | GoogleScholarGoogle Scholar |
[41] Q. Wang, Q. Liu, J. Li, Tissue distribution and elimination of oxytetracycline in perch Lateolabras janopicus and black seabream (Sparus macrocephalus) following oral administration. Aquaculture 2004, 237, 31.
| Tissue distribution and elimination of oxytetracycline in perch Lateolabras janopicus and black seabream (Sparus macrocephalus) following oral administration.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2cXls1Wrsbs%3D&md5=27e4e8d846b2b6211ff0964e0048ff1aCAS |
[42] J. Dingemanse, F. A. E. Sollie, D. D. Breimer, M. Danhof, Pharmacokinetic modeling of the anticonvulsant response of oxazepam in rats using the pentylenetetrazol threshold concentration as pharmacodynamic measure. J. Pharmacokinet. Biopharm. 1988, 16, 203.
| Pharmacokinetic modeling of the anticonvulsant response of oxazepam in rats using the pentylenetetrazol threshold concentration as pharmacodynamic measure.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaL1cXltVCisrY%3D&md5=da0b6e700bd91e6a7d7c1bf5bcda3620CAS | 3418496PubMed |
[43] E. P. Wala, W. R. Martin, J. W. Sloan, Brain-plasma distribution of free and total benzodiazepines in dogs physically dependent on different doses of diazepam. Pharmacol. Biochem. Behav. 1995, 52, 707.
| Brain-plasma distribution of free and total benzodiazepines in dogs physically dependent on different doses of diazepam.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK2MXpsVGrtrw%3D&md5=721060f59474c43bcbc5d23a1df13f3bCAS | 8587909PubMed |
[44] N. Cartiser, F. Bevalot, C. LeMeur, Y. Gaillard, D. Malicier, N. Hubert, J. Guitton, Gas chromatography–tandem mass spectrometry assay for the quantification of four benzodiazepines and citalopram in eleven post-mortem rabbit fluids and tissues, with application to animal and human samples. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 2011, 879, 2909.
| Gas chromatography–tandem mass spectrometry assay for the quantification of four benzodiazepines and citalopram in eleven post-mortem rabbit fluids and tissues, with application to animal and human samples.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3MXhtF2kur%2FL&md5=601e4baafd60c687afe26277e979a59fCAS | 21907645PubMed |
[45] T. B. Thorson, The partitioning of body water in osteichthyes: phylogenetic and ecological implications in aquatic vertebrates. Biol. Bull. 1961, 120, 238.
| The partitioning of body water in osteichthyes: phylogenetic and ecological implications in aquatic vertebrates.Crossref | GoogleScholarGoogle Scholar |
[46] J. Feldschuh, Y. Enson, Prediction of the normal blood volume. Relation of blood volume to body habitus. Circulation 1977, 56, 605.
| Prediction of the normal blood volume. Relation of blood volume to body habitus.Crossref | GoogleScholarGoogle Scholar | 1:STN:280:DyaE1c%2Fgt1emuw%3D%3D&md5=9d20c0a26021155fe9baa0cfa23cf285CAS | 902387PubMed |
[47] M. Schultz, A. Schmoldt, Therapeutic and toxic blood concentrations of more than 800 drugs and other xenobiotics. Pharmazie 2003, 58, 447.
