Pharmacokinetic Modeling of Paracetamol Uptake and Clearance in Zebrafish Larvae: Expanding the Allometric Scale in Vertebrates with Five Orders of Magnitude.
Pharmacokinetic Modeling of Paracetamol Uptake and Clearance in Zebrafish Larvae: Expanding the Allometric Scale in Vertebrates with Five Orders of Magnitude.
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DOI：
10.1089/zeb.2016.1313
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发表时间：
2016-12
期刊：
影响因子：
2
通讯作者：
Hankemeier T
中科院分区：
文献类型：
--
作者：
Kantae V;Krekels EH;Ordas A;González O;van Wijk RC;Harms AC;Racz PI;van der Graaf PH;Spaink HP;Hankemeier T
斑马鱼幼虫（Danio rerio）越来越多地用于将体外试验中关于药物疗效和安全性的发现转化为脊椎动物物种，包括人类。然而，对该物种药物暴露的有限了解阻碍了其在转化研究中的实施。使用扑热息痛作为一个范例化合物，我们提出了一种新的方法来表征在斑马鱼幼虫的药代动力学过程，通过结合敏感的生物分析方法和非线性混合效应模型。所开发的方法允许对乙酰氨基酚及其两种主要代谢产物，对乙酰氨基酚硫酸盐和对乙酰氨基酚葡萄糖醛酸苷的5个裂解的斑马鱼幼虫受精后3天的合并样品的定量。对乙酰氨基酚药物摄取定量为0.289 pmole/min，对乙酰氨基酚清除定量为幼虫总值的1.7%。平均体积确定为0.290 μL，得出绝对清除率为2.96 × 107 L/h，与高等脊椎动物的清除率相当。开发的方法将提高成功率的药物筛选在斑马鱼幼虫和翻译潜力的调查结果，允许建立准确的暴露曲线，从而也建立浓度-效应关系。
Zebrafish larvae (Danio rerio) are increasingly used to translate findings regarding drug efficacy and safety from in vitro-based assays to vertebrate species, including humans. However, the limited understanding of drug exposure in this species hampers its implementation in translational research. Using paracetamol as a paradigm compound, we present a novel method to characterize pharmacokinetic processes in zebrafish larvae, by combining sensitive bioanalytical methods and nonlinear mixed effects modeling. The developed method allowed quantification of paracetamol and its two major metabolites, paracetamol-sulfate and paracetamol-glucuronide in pooled samples of five lysed zebrafish larvae of 3 days post-fertilization. Paracetamol drug uptake was quantified to be 0.289 pmole/min and paracetamol clearance was quantified to be 1.7% of the total value of the larvae. With an average volume determined to be 0.290 μL, this yields an absolute clearance of 2.96 × 107 L/h, which scales reasonably well with clearance rates in higher vertebrates. The developed methodology will improve the success rate of drug screens in zebrafish larvae and the translation potential of findings, by allowing the establishment of accurate exposure profiles and thereby also the establishment of concentration–effect relationships.
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影响因子：
6.1
作者：
Lindbom, L;Pihlgren, P;Jonsson, N
通讯作者：
Jonsson, N
影响因子：
3.6
作者：
Raterink, Robert-Jan;van der Kloet, Frans Meindert;Hankemeier, Thomas
通讯作者：
Hankemeier, Thomas
影响因子：
1.8
作者：
Alderton, W.;Berghmans, S.;Gardner, I.
通讯作者：
Gardner, I.
影响因子：
--
作者：
Chng, Hui Ting;Ho, Han Kiat;Chan, Eric Chun Yong
通讯作者：
Chan, Eric Chun Yong
影响因子：
3.8
作者：
Allegaert, K;De Hoon, J;Tibboel, D
通讯作者：
Tibboel, D