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, nor...鱼类是药物发现、药物安全评估及环境毒理学领域中，用于人类药物药理学与毒理学表征的重要模式生物。为解答“鱼类对药物的响应是否与人类一致”这一科学问题，我们基于“相似的血浆药物浓度在生物组织层次相近的人类与鱼类体内可引发等效的靶标介导效应”这一交叉参照假说（Read-Across Hypothesis），提出了一种全新的定量跨物种外推方法（qCSE）。为验证该假说，本研究以抗抑郁药物氟西汀对模式鱼类黑头软口鲦（Pimephales promelas）的行为效应作为验证案例：将鱼类暴露于一系列实测浓度的氟西汀水体中（0.1、1.0、8.0、16、32、64 μg/L），使鱼类的血浆药物浓度分别覆盖人类治疗血浆浓度范围（Human Therapeutic Plasma Concentrations, HTPCs）的下沿、区间与上沿，暴露时长为28天。氟西汀及其代谢产物去甲氟西汀（原文此处截断为nor...）