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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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Relationship between plasma concentrations of fluoxetine and its effects on fish exploratory behaviour after 28 days of exposure.Exploratory behaviour was quantified in individual fish using the Novel Tank Diving Test. A) Number of transitions into the Top Area; B) number of transitions into the Middle Area; C) time spent in the Top Area; D) time spent in the Middle Area; E) distance travelled in the Top Area; F) distance travelled in the Middle Area; G) speed. The Human Therapeutic Plasma Concentration range of fluoxetine plotted in the graphs is 91–302 ng/mL. C1 and C2 indicate control group 1 and control group 2, respectively. The X-axis has a Log2 scale, while the Y-axis has a linear scale. Values are plotted as mean ± SD (n = 20). *: p<0.05.
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pone-0110467-g004: Relationship between plasma concentrations of fluoxetine and its effects on fish exploratory behaviour after 28 days of exposure.Exploratory behaviour was quantified in individual fish using the Novel Tank Diving Test. A) Number of transitions into the Top Area; B) number of transitions into the Middle Area; C) time spent in the Top Area; D) time spent in the Middle Area; E) distance travelled in the Top Area; F) distance travelled in the Middle Area; G) speed. The Human Therapeutic Plasma Concentration range of fluoxetine plotted in the graphs is 91–302 ng/mL. C1 and C2 indicate control group 1 and control group 2, respectively. The X-axis has a Log2 scale, while the Y-axis has a linear scale. Values are plotted as mean ± SD (n = 20). *: p<0.05.

Mentions: On day 28, fish exposed to the two highest concentrations of fluoxetine (38 and 72 µg/L) explored the upper areas of the novel environment more frequently and for longer time compared to the fish in the other groups, confirming the anxiolytic effects of fluoxetine in fish observed on Day 14 (Figure 4, Figure 5, Figure 6, Figure 7). Of the seven behavioural endpoints considered in this study, all except Speed were significantly affected in fish exposed to 72 µg fluoxetine/L (p<0.01 for all the affected endpoints except for the distance Dist-Middle, for which p = 0.017), whereas the exposure to 38 µg fluoxetine/L significantly affected only the endpoints related to the Middle Area (T-Middle, p = 0.03; Time-Middle, p = 0.013; Dist-Middle, p = 0.016) (Figure 4). These results suggest that 38 µg fluoxetine/L induced the fish to swim more frequently in the Middle Area, but this effect was not strong enough to induce fish to swim in the Top Area of the observation tank (the furthest from the “safe” bottom area).


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)

Relationship between plasma concentrations of fluoxetine and its effects on fish exploratory behaviour after 28 days of exposure.Exploratory behaviour was quantified in individual fish using the Novel Tank Diving Test. A) Number of transitions into the Top Area; B) number of transitions into the Middle Area; C) time spent in the Top Area; D) time spent in the Middle Area; E) distance travelled in the Top Area; F) distance travelled in the Middle Area; G) speed. The Human Therapeutic Plasma Concentration range of fluoxetine plotted in the graphs is 91–302 ng/mL. C1 and C2 indicate control group 1 and control group 2, respectively. The X-axis has a Log2 scale, while the Y-axis has a linear scale. Values are plotted as mean ± SD (n = 20). *: p<0.05.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0110467-g004: Relationship between plasma concentrations of fluoxetine and its effects on fish exploratory behaviour after 28 days of exposure.Exploratory behaviour was quantified in individual fish using the Novel Tank Diving Test. A) Number of transitions into the Top Area; B) number of transitions into the Middle Area; C) time spent in the Top Area; D) time spent in the Middle Area; E) distance travelled in the Top Area; F) distance travelled in the Middle Area; G) speed. The Human Therapeutic Plasma Concentration range of fluoxetine plotted in the graphs is 91–302 ng/mL. C1 and C2 indicate control group 1 and control group 2, respectively. The X-axis has a Log2 scale, while the Y-axis has a linear scale. Values are plotted as mean ± SD (n = 20). *: p<0.05.
Mentions: On day 28, fish exposed to the two highest concentrations of fluoxetine (38 and 72 µg/L) explored the upper areas of the novel environment more frequently and for longer time compared to the fish in the other groups, confirming the anxiolytic effects of fluoxetine in fish observed on Day 14 (Figure 4, Figure 5, Figure 6, Figure 7). Of the seven behavioural endpoints considered in this study, all except Speed were significantly affected in fish exposed to 72 µg fluoxetine/L (p<0.01 for all the affected endpoints except for the distance Dist-Middle, for which p = 0.017), whereas the exposure to 38 µg fluoxetine/L significantly affected only the endpoints related to the Middle Area (T-Middle, p = 0.03; Time-Middle, p = 0.013; Dist-Middle, p = 0.016) (Figure 4). These results suggest that 38 µg fluoxetine/L induced the fish to swim more frequently in the Middle Area, but this effect was not strong enough to induce fish to swim in the Top Area of the observation tank (the furthest from the “safe” bottom area).

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