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

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.

鱼类是药物研发、药物安全评价及环境毒理学领域中，用于人类药物药理与毒理学表征的重要模式生物。然而，鱼类对药物的响应是否与人类一致？为解答这一问题，我们基于“相似的血浆药物浓度在生物组织水平相近的人类与鱼类体内可引发相当的靶点介导效应”这一交叉对照假说（Read-Across Hypothesis），提出了一种全新的定量跨物种外推方法（quantitative cross-species extrapolation, qCSE）。为验证该假说，我们以抗抑郁药物氟西汀（fluoxetine）对模式生物黑头呆鱼（Pimephales promelas）的行为效应作为验证案例。将鱼类暴露于一系列实测水体氟西汀浓度（0.1、1.0、8.0、16、32、64 μg/L）中，暴露时长为28天，以此获得低于、等于及高于人体治疗血浆浓度范围（Human Therapeutic Plasma Concentrations, HTPCs）的血浆药物浓度。对单尾鱼类血浆中的氟西汀及其代谢物去甲氟西汀（norfluoxetine）进行定量检测，并将检测结果与焦虑相关行为终点进行关联分析。结果显示，在鱼类体内引发抗焦虑应答的最低血浆药物浓度高于HTPCs的上限值，而当血浆浓度低于HTPCs范围时未观察到任何效应。人类与鱼类体内氟西汀的体内代谢过程相似，均呈现由自身抑制动力学及将氟西汀转化为去甲氟西汀的酶的饱和效应所驱动的双相浓度依赖性动力学特征。鱼类对氟西汀的敏感性与广泛性焦虑障碍患者的敏感性并无显著差异。本研究结果首次提供了在鱼类体内测得的药物内剂量响应效应的直接证据，由此验证了应用于氟西汀的交叉对照假说。总体而言，本研究证实，以内在药物浓度为基准的qCSE方法是评估鱼类对药物敏感性的有力工具，并提升了跨物种外推的转化效力。