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Quantitative cross-species extrapolation between humans and fish: the case of the anti-depressant fluoxetine.

Margiotta-Casaluci L, Owen SF, Cumming RI, de Polo A, Winter MJ, Panter GH, Rand-Weaver M, Sumpter JP - PLoS ONE (2014)

Bottom Line: 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.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.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.

View Article: PubMed Central - PubMed

Affiliation: Institute for the Environment, Brunel University, London, United Kingdom; AstraZeneca, Global Environment, Freshwater Quarry, Brixham, United Kingdom.

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.

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Related in: MedlinePlus

Methodological procedure for the quantification of fish behaviour.A) Experimental steps performed to quantify fish behavioural response to a new environment following 14-day and 28-day exposure to fluoxetine. Anxiety-related behavioural endpoints were quantified using a Novel Tank Diving Test. B) Example of different exploratory behaviours in a Novel Tank Diving Test. Inactive fish (left) versus active fish (right). The different tracking colours indicate different speeds (black, slow; green, medium; red, fast).
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pone-0110467-g001: Methodological procedure for the quantification of fish behaviour.A) Experimental steps performed to quantify fish behavioural response to a new environment following 14-day and 28-day exposure to fluoxetine. Anxiety-related behavioural endpoints were quantified using a Novel Tank Diving Test. B) Example of different exploratory behaviours in a Novel Tank Diving Test. Inactive fish (left) versus active fish (right). The different tracking colours indicate different speeds (black, slow; green, medium; red, fast).

Mentions: The “Novel Tank Diving Test” is conceptually similar to the rodent open field test. It is based on the instinctive behaviour of fish to seek protection when they are transferred to a novel and unfamiliar environment (i.e. observation tank) by diving to the bottom and remaining in an alert status until the environmental conditions are perceived as safe enough to initiate exploration of the new environment. In this test, fish are individually transferred from the home tank to the novel environment, which is represented by a clean observation tank containing water that has not previously been exposed to other fish. The swimming pattern is then analysed by separating the main area into two or three different sub-areas (e.g. bottom, middle, top) in post hoc video analysis (Figure 1). Several behavioural endpoints are quantified to assess anxiety (e.g. number of transitions into the top area, time spent in the top area). Many of these endpoints are strictly correlated with the height at which the fish swims in the tank (Figure 1). This measure is considered a very powerful measure of anxiety, and notably, it can be compared to the thymogtaxis observed in rodents, defined as the response of an organism to physical contact or to the proximity of a physical discontinuity in the environment (e.g. rats preferring to swim near the edge of a water maze) [29].


Quantitative cross-species extrapolation between humans and fish: the case of the anti-depressant fluoxetine.

Margiotta-Casaluci L, Owen SF, Cumming RI, de Polo A, Winter MJ, Panter GH, Rand-Weaver M, Sumpter JP - PLoS ONE (2014)

Methodological procedure for the quantification of fish behaviour.A) Experimental steps performed to quantify fish behavioural response to a new environment following 14-day and 28-day exposure to fluoxetine. Anxiety-related behavioural endpoints were quantified using a Novel Tank Diving Test. B) Example of different exploratory behaviours in a Novel Tank Diving Test. Inactive fish (left) versus active fish (right). The different tracking colours indicate different speeds (black, slow; green, medium; red, fast).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4206295&req=5

pone-0110467-g001: Methodological procedure for the quantification of fish behaviour.A) Experimental steps performed to quantify fish behavioural response to a new environment following 14-day and 28-day exposure to fluoxetine. Anxiety-related behavioural endpoints were quantified using a Novel Tank Diving Test. B) Example of different exploratory behaviours in a Novel Tank Diving Test. Inactive fish (left) versus active fish (right). The different tracking colours indicate different speeds (black, slow; green, medium; red, fast).
Mentions: The “Novel Tank Diving Test” is conceptually similar to the rodent open field test. It is based on the instinctive behaviour of fish to seek protection when they are transferred to a novel and unfamiliar environment (i.e. observation tank) by diving to the bottom and remaining in an alert status until the environmental conditions are perceived as safe enough to initiate exploration of the new environment. In this test, fish are individually transferred from the home tank to the novel environment, which is represented by a clean observation tank containing water that has not previously been exposed to other fish. The swimming pattern is then analysed by separating the main area into two or three different sub-areas (e.g. bottom, middle, top) in post hoc video analysis (Figure 1). Several behavioural endpoints are quantified to assess anxiety (e.g. number of transitions into the top area, time spent in the top area). Many of these endpoints are strictly correlated with the height at which the fish swims in the tank (Figure 1). This measure is considered a very powerful measure of anxiety, and notably, it can be compared to the thymogtaxis observed in rodents, defined as the response of an organism to physical contact or to the proximity of a physical discontinuity in the environment (e.g. rats preferring to swim near the edge of a water maze) [29].

Bottom Line: 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.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.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.

View Article: PubMed Central - PubMed

Affiliation: Institute for the Environment, Brunel University, London, United Kingdom; AstraZeneca, Global Environment, Freshwater Quarry, Brixham, United Kingdom.

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.

Show MeSH
Related in: MedlinePlus