NDLI: Quantitative Cross-Species Extrapolation between Humans and Fish: The Case of the Anti-Depressant Fluoxetine

Content Provider	PubMed Central
Author	Luigi, Margiotta-casaluci Owen, Stewart F. Cumming, Rob I. Polo, Anna De Winter, Matthew J. Panter, Grace H. Rand-weaver, Mariann Sumpter, John P.
Editor	Pawluski, Jodi
Copyright Year	2014
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 (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.
Related Links	http://dx.doi.org/10.1371/journal.pone.0110467
Starting Page	110467
File Format	PDF
ISSN	19326203
e-ISSN	19326203
Journal	PLoS ONE
Issue Number	10
Volume Number	9
Language	English
Publisher	Public Library of Science
Publisher Date	2014-10-22
Access Restriction	Open
Rights Holder	Public Library of Science
Subject Keyword	Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
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Data from: Quantitative cross-species extrapolation between humans and fish: the case of the anti-depressant fluoxetine (Dataset)

The apparently very variable potency of the anti-depressant fluoxetine.

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Data from: Quantitative cross-species extrapolation between humans and fish: the case of the anti-depressant fluoxetine (Dataset)

The apparently very variable potency of the anti-depressant fluoxetine.

Chemical dampening of Ly6Chi monocytes in the periphery produces anti-depressant effects in mice

Measured Copper Toxicity to Cnesterodon decemmaculatus (Pisces: Poeciliidae) and Predicted by Biotic Ligand Model in Pilcomayo River Water: A Step for a Cross-Fish-Species Extrapolation

Fluvoxamine, an anti-depressant, inhibits human glioblastoma invasion by disrupting actin polymerization

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Quantitative Cross-Species Extrapolation between Humans and Fish: The Case of the Anti-Depressant Fluoxetine