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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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Fluoxetine uptake and metabolism in fathead minnow following a 28-d study.A) Relationship between measured (red line; mean ± SD; n = 20) and predicted (dashed line) plasma concentrations of fluoxetine, based on concentrations quantified in the water. The predicted plasma concentrations were generated by using the Fish Plasma Model [18]. B) Relationship between measured plasma concentrations of fluoxetine (red line; mean ± SD; n = 20) and norfluoxetine:fluoxetine ratio (grey line, mean ± SD; n = 20). The change in the slope of the plasma concentration curve corresponds to the decrease of the norfluoxetine:fluoxetine ratio, indicating inhibitory and/or saturation effects on the metabolic enzymes that convert fluoxetine into norfluoxetine. C) Relationship between measured plasma concentrations of fluoxetine in fish plasma (mean ± SD; n = 20) and Human Therapeutic Plasma Concentration range (grey area, 91–302 ng/mL). D) Relationship between measured plasma concentrations of norfluoxetine in fish plasma (mean ± SD; n = 20) and Human Therapeutic Plasma Concentration range (grey area, 72–258 ng/mL).
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pone-0110467-g002: Fluoxetine uptake and metabolism in fathead minnow following a 28-d study.A) Relationship between measured (red line; mean ± SD; n = 20) and predicted (dashed line) plasma concentrations of fluoxetine, based on concentrations quantified in the water. The predicted plasma concentrations were generated by using the Fish Plasma Model [18]. B) Relationship between measured plasma concentrations of fluoxetine (red line; mean ± SD; n = 20) and norfluoxetine:fluoxetine ratio (grey line, mean ± SD; n = 20). The change in the slope of the plasma concentration curve corresponds to the decrease of the norfluoxetine:fluoxetine ratio, indicating inhibitory and/or saturation effects on the metabolic enzymes that convert fluoxetine into norfluoxetine. C) Relationship between measured plasma concentrations of fluoxetine in fish plasma (mean ± SD; n = 20) and Human Therapeutic Plasma Concentration range (grey area, 91–302 ng/mL). D) Relationship between measured plasma concentrations of norfluoxetine in fish plasma (mean ± SD; n = 20) and Human Therapeutic Plasma Concentration range (grey area, 72–258 ng/mL).

Mentions: The uptake followed a bi-phasic concentration-dependent kinetics (Figure 2). The lowest fluoxetine water concentrations that produced quantifiable levels of fluoxetine and norlfuoxetine in individual plasma samples was 10 µg fluoxetine/L. In this treatment group the measured plasma concentrations were very close to those predicted by the FPM, which was therefore also used to predict plasma concentrations for the 0.1 and 1 µg/L treatment groups. At water concentrations between 0.1 and 20 µg/L the linear uptake was driven by the Log D7.4, as demonstrated by the high accuracy of the FPM. However, at water concentrations higher than 20 µg/L, the slope of the linear uptake changed significantly (from 4.3 to 15.5), so that the measured plasma concentrations were higher than those predicted. At 10 µg/L the mean measured plasma concentrations were only 14% higher than the predicted ones. This value increased to 32% at 20 µg/L, 63% at 38 µg/L, and 71% at 72 µg/L.


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)

Fluoxetine uptake and metabolism in fathead minnow following a 28-d study.A) Relationship between measured (red line; mean ± SD; n = 20) and predicted (dashed line) plasma concentrations of fluoxetine, based on concentrations quantified in the water. The predicted plasma concentrations were generated by using the Fish Plasma Model [18]. B) Relationship between measured plasma concentrations of fluoxetine (red line; mean ± SD; n = 20) and norfluoxetine:fluoxetine ratio (grey line, mean ± SD; n = 20). The change in the slope of the plasma concentration curve corresponds to the decrease of the norfluoxetine:fluoxetine ratio, indicating inhibitory and/or saturation effects on the metabolic enzymes that convert fluoxetine into norfluoxetine. C) Relationship between measured plasma concentrations of fluoxetine in fish plasma (mean ± SD; n = 20) and Human Therapeutic Plasma Concentration range (grey area, 91–302 ng/mL). D) Relationship between measured plasma concentrations of norfluoxetine in fish plasma (mean ± SD; n = 20) and Human Therapeutic Plasma Concentration range (grey area, 72–258 ng/mL).
© Copyright Policy
Related In: Results  -  Collection

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

pone-0110467-g002: Fluoxetine uptake and metabolism in fathead minnow following a 28-d study.A) Relationship between measured (red line; mean ± SD; n = 20) and predicted (dashed line) plasma concentrations of fluoxetine, based on concentrations quantified in the water. The predicted plasma concentrations were generated by using the Fish Plasma Model [18]. B) Relationship between measured plasma concentrations of fluoxetine (red line; mean ± SD; n = 20) and norfluoxetine:fluoxetine ratio (grey line, mean ± SD; n = 20). The change in the slope of the plasma concentration curve corresponds to the decrease of the norfluoxetine:fluoxetine ratio, indicating inhibitory and/or saturation effects on the metabolic enzymes that convert fluoxetine into norfluoxetine. C) Relationship between measured plasma concentrations of fluoxetine in fish plasma (mean ± SD; n = 20) and Human Therapeutic Plasma Concentration range (grey area, 91–302 ng/mL). D) Relationship between measured plasma concentrations of norfluoxetine in fish plasma (mean ± SD; n = 20) and Human Therapeutic Plasma Concentration range (grey area, 72–258 ng/mL).
Mentions: The uptake followed a bi-phasic concentration-dependent kinetics (Figure 2). The lowest fluoxetine water concentrations that produced quantifiable levels of fluoxetine and norlfuoxetine in individual plasma samples was 10 µg fluoxetine/L. In this treatment group the measured plasma concentrations were very close to those predicted by the FPM, which was therefore also used to predict plasma concentrations for the 0.1 and 1 µg/L treatment groups. At water concentrations between 0.1 and 20 µg/L the linear uptake was driven by the Log D7.4, as demonstrated by the high accuracy of the FPM. However, at water concentrations higher than 20 µg/L, the slope of the linear uptake changed significantly (from 4.3 to 15.5), so that the measured plasma concentrations were higher than those predicted. At 10 µg/L the mean measured plasma concentrations were only 14% higher than the predicted ones. This value increased to 32% at 20 µg/L, 63% at 38 µg/L, and 71% at 72 µg/L.

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