title: Quantitative cross-species extrapolation between humans and fish: the case of the anti-depressant fluoxetine.
abstract: Fish 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 (H(T)PCs). 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 H(T)PC range, whereas no effects were observed at plasma concentrations below the H(T)PCs. 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.
authors.affiliation: Institute for the Environment, Brunel University, London, United Kingdom; AstraZeneca, Global Environment, Freshwater Quarry, Brixham, United Kingdom.
authors.forename: Luigi
authors.initials: L
authors.lastname: Margiotta-Casaluci
authors.affiliation: AstraZeneca, Global Environment, Freshwater Quarry, Brixham, United Kingdom.
authors.forename: Stewart F
authors.initials: SF
authors.lastname: Owen
authors.affiliation: AstraZeneca, Global Environment, Freshwater Quarry, Brixham, United Kingdom.
authors.forename: Rob I
authors.initials: RI
authors.lastname: Cumming
authors.affiliation: Institute for the Environment, Brunel University, London, United Kingdom.
authors.forename: Anna
authors.initials: A
authors.lastname: de Polo
authors.affiliation: AstraZeneca, Global Environment, Freshwater Quarry, Brixham, United Kingdom.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Winter
authors.affiliation: AstraZeneca, Global Environment, Freshwater Quarry, Brixham, United Kingdom.
authors.forename: Grace H
authors.initials: GH
authors.lastname: Panter
authors.affiliation: Biosciences, School of Health Sciences and Social Care, Brunel University, London, United Kingdom.
authors.forename: Mariann
authors.initials: M
authors.lastname: Rand-Weaver
authors.affiliation: Institute for the Environment, Brunel University, London, United Kingdom.
authors.forename: John P
authors.initials: JP
authors.lastname: Sumpter
mesh_terms: D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D001007:Anxiety / Q000188:drug therapy; D001522:Behavior, Animal / Q000187:drug effects; D001711:Biotransformation; D003530:Cyprinidae; D004305:Dose-Response Relationship, Drug; D005473:Fluoxetine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D006801:Humans; D008297:Male; D014741:Video Recording
chemical_list: D018687:Antidepressive Agents, Second-Generation; D005473:Fluoxetine; C036139:norfluoxetine