Quantitative cross-species extrapolation between humans and fish: the case of the anti-depressant fluoxetine.
Quantitative cross-species extrapolation between humans and fish: the case of the anti-depressant fluoxetine.
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DOI：
10.1371/journal.pone.0110467
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Sumpter JP
中科院分区：
文献类型：
--
作者：
Margiotta-Casaluci L;Owen SF;Cumming RI;de Polo A;Winter MJ;Panter GH;Rand-Weaver M;Sumpter JP
在药物发现、药物安全性评价和环境毒理学方面，鱼类是人类药物药理和毒理学表征的重要模型。然而，鱼类对药物的反应和人类一样吗？为了解决这个问题，我们提出了一种新的定量跨物种外推方法（qCSE），该方法基于一个假设，即在相似的生物组织水平上，相似的血浆浓度的药物会在人类和鱼类中引起类似的靶介导效应（Read-Across假说）。为了验证这一假设，我们以抗抑郁药物氟西汀对鱼模型黑头鲦鱼（Pimephales promelas）的行为影响作为实验案例。将鱼暴露在测定的氟西汀水中浓度范围（0.1、1.0、8.0、16、32、64µg/L）中28天，产生的血浆浓度低于、等于和高于人类治疗血浆浓度（HTPCs）范围。氟西汀及其代谢物去甲氟西汀在个体鱼的血浆中被量化，并与行为焦虑相关的终点相关联。引起鱼类焦虑反应的最低血浆药物浓度高于HTPC范围的上限，而低于HTPC的血浆浓度则没有观察到任何影响。氟西汀在人体内和鱼体内的代谢是相似的，并且表现出双相浓度依赖动力学，由自抑制动力学和将氟西汀转化为去甲氟西汀的酶的饱和驱动。鱼类对氟西汀的敏感性与受一般焦虑症影响的患者没有太大的不同。这些结果首次直接证明了一种药物在鱼类体内的内剂量反应效应，从而验证了氟西汀的跨读假说。总体而言，本研究表明，基于内部药物浓度的qCSE方法是指导鱼类对药物敏感性评估的有力工具，并增强了跨物种外推的翻译能力。
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.
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影响因子：
2.7
作者：
Egan, Rupert J.;Bergner, Carisa L.;Hart, Peter C.;Cachat, Jonathan M.;Canavello, Peter R.;Elegante, Marco F.;Elkhayat, Salem I.;Bartels, Brett K.;Tien, Anna K.;Tien, David H.;Mohnot, Sopan;Beeson, Esther;Glasgow, Eric;Amri, Hakima;Zukowska, Zofia;Kalueff, Allan V.
通讯作者：
Kalueff, Allan V.
影响因子：
8.8
作者：
Caldwell, Daniel J.;Mastrocco, Frank;Brooks, Bryan W.
通讯作者：
Brooks, Bryan W.
影响因子：
11.4
作者：
Gunnarsson, Lina;Jauhiainen, Alexandra;Larsson, D. G. Joakim
通讯作者：
Larsson, D. G. Joakim
DOI：
10.1097/00008571-199902000-00008
发表时间：
1999-02-01
期刊：
PHARMACOGENETICS
影响因子：
--
作者：
Fjordside, L;Jeppesen, U;Brosen, K
通讯作者：
Brosen, K
影响因子：
4.4
作者：
Goldstone JV;McArthur AG;Kubota A;Zanette J;Parente T;Jönsson ME;Nelson DR;Stegeman JJ
通讯作者：
Stegeman JJ