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.
Highlights
Cross-species extrapolation of biological processes represents a cornerstone in pharmacology and toxicology, both of which are intimately dependent on its reliability to accurately predict therapeutic and harmful effects of chemical substances in humans or other recipient species
On the other hand, when the extrapolation is aimed at the environmental risk assessment (ERA) of chemicals applied to wildlife the results of toxicity experiments, conducted using a limited selection of test species, are extrapolated to tens or hundreds of species potentially living within the same ecosystem [7]
Overall we show that the quantitative cross-species extrapolation approach (qCSE) approach, anchored to the plasma concentration of drug, 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
Summary
Cross-species extrapolation of biological processes represents a cornerstone in pharmacology and toxicology, both of which are intimately dependent on its reliability to accurately predict therapeutic and harmful effects of chemical substances in humans or other recipient species. The increasing number of pharmaceuticals detected in surface waters (e.g. rivers) has attracted interest in recent years because these compounds, despite being present at very low concentrations (sub-ng/L to few mg/L), are selected to interact with high affinity with specific human biological targets (e.g. receptors, enzymes) These targets can be evolutionary conserved and functional in aquatic organisms (especially in fish) [12], suggesting that the interaction drug/target may theoretically lead to unwanted pharmacological (and potentially toxicological) effects in non-target species exposed to pharmaceuticals in the environment. This approach centres on the exploitation of clinical and non-clinical data to predict potential effects in wildlife species, and it has been praised by a number of authors over recent years, with respect to fish [11,13,14,15]
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