Please use this identifier to cite or link to this item: http://buratest.brunel.ac.uk/handle/2438/9555
Full metadata record
DC FieldValueLanguage
dc.contributor.authorMargiotta-Casaluci, L-
dc.contributor.authorOwen, SF-
dc.contributor.authorCumming, RI-
dc.contributor.authorDe Polo, A-
dc.contributor.authorWinter, MJ-
dc.contributor.authorPanter, GH-
dc.contributor.authorRand-Weaver, M-
dc.contributor.authorSumpter, JP-
dc.date.accessioned2014-12-18T13:53:27Z-
dc.date.available2014-10-22-
dc.date.available2014-12-18T13:53:27Z-
dc.date.issued2014-
dc.identifier.citationPLoS ONE, 9: (10) 2014en_US
dc.identifier.issn1932-6203-
dc.identifier.urihttp://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0110467-
dc.identifier.urihttp://bura.brunel.ac.uk/handle/2438/9555-
dc.descriptionThis article has been made available through the Brunel Open Access Publishing Fund.-
dc.description.abstractFish are an important model for the pharmacological and toxicological characterization of human pharmaceuticals in drug discovery, drug safety assessment and environmental toxicology. However, do fish respond to pharmaceuticals as humans do? To address this question, we provide a novel quantitative cross-species extrapolation approach (qCSE) based on the hypothesis that similar plasma concentrations of pharmaceuticals cause comparable target-mediated effects in both humans and fish at similar level of biological organization (Read-Across Hypothesis). To validate this hypothesis, the behavioural effects of the anti-depressant drug fluoxetine on the fish model fathead minnow (Pimephales promelas) were used as test case. Fish were exposed for 28 days to a range of measured water concentrations of fluoxetine (0.1, 1.0, 8.0, 16, 32, 64 μg/L) to produce plasma concentrations below, equal and above the range of Human Therapeutic Plasma Concentrations (HTPCs). Fluoxetine and its metabolite, norfluoxetine, were quantified in the plasma of individual fish and linked to behavioural anxiety-related endpoints. The minimum drug plasma concentrations that elicited anxiolytic responses in fish were above the upper value of the HTPC range, whereas no effects were observed at plasma concentrations below the HTPCs. In vivo metabolism of fluoxetine in humans and fish was similar, and displayed bi-phasic concentration-dependent kinetics driven by the auto-inhibitory dynamics and saturation of the enzymes that convert fluoxetine into norfluoxetine. The sensitivity of fish to fluoxetine was not so dissimilar from that of patients affected by general anxiety disorders. These results represent the first direct evidence of measured internal dose response effect of a pharmaceutical in fish, hence validating the Read-Across hypothesis applied to fluoxetine. Overall, this study demonstrates that the qCSE approach, anchored to internal drug concentrations, is a powerful tool to guide the assessment of the sensitivity of fish to pharmaceuticals, and strengthens the translational power of the cross-species extrapolation.en_US
dc.languageeng-
dc.language.isoenen_US
dc.publisherPublic Library of Scienceen_US
dc.subjectPharmacological and toxicological characterizationen_US
dc.subjectDrug safety assessmenten_US
dc.subjectEnvironmental toxicologyen_US
dc.subjectQuantitative cross-species extrapolation (qCSE)en_US
dc.subjectFluoxetineen_US
dc.subjectRead-Across Hypothesisen_US
dc.titleQuantitative cross-species extrapolation between humans and fish: The case of the anti-depressant fluoxetineen_US
dc.typeArticleen_US
dc.identifier.doihttp://dx.doi.org/10.1371/journal.pone.0110467-
dc.relation.isPartOfPLoS ONE-
dc.relation.isPartOfPLoS ONE-
pubs.organisational-data/Brunel-
pubs.organisational-data/Brunel/Brunel Staff by College/Department/Division-
pubs.organisational-data/Brunel/Brunel Staff by College/Department/Division/College of Health and Life Sciences-
pubs.organisational-data/Brunel/Brunel Staff by College/Department/Division/College of Health and Life Sciences/Dept of Clinical Sciences-
pubs.organisational-data/Brunel/Brunel Staff by College/Department/Division/College of Health and Life Sciences/Dept of Clinical Sciences/Community Health and Public Health-
pubs.organisational-data/Brunel/Brunel Staff by College/Department/Division/College of Health and Life Sciences/Dept of Life Sciences-
pubs.organisational-data/Brunel/Brunel Staff by College/Department/Division/College of Health and Life Sciences/Dept of Life Sciences/Biological Sciences-
pubs.organisational-data/Brunel/Brunel Staff by Institute/Theme-
pubs.organisational-data/Brunel/Brunel Staff by Institute/Theme/Institute of Environmental, Health and Societies-
pubs.organisational-data/Brunel/Brunel Staff by Institute/Theme/Institute of Environmental, Health and Societies/Health and Environment-
pubs.organisational-data/Brunel/Specialist Centres-
pubs.organisational-data/Brunel/Specialist Centres/IfE-
Appears in Collections:Brunel OA Publishing Fund
Institute for the Environment



Items in BURA are protected by copyright, with all rights reserved, unless otherwise indicated.