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      Impact of post-hatching maturation on the pharmacokinetics of paracetamol in zebrafish larvae

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          Abstract

          Zebrafish larvae are increasingly used in pharmacological and toxicological studies, but it is often overlooked that internal exposure to exogenous compounds, rather than the incubation medium concentration, is driving observed effects. Moreover, as the zebrafish larva is a developing organism, continuous physiological changes impact pharmacokinetic or toxicokinetic processes like the absorption and elimination of exogenous compounds, influencing the interpretation of observations and conclusions drawn from experiments at different larval ages. Here, using paracetamol as paradigm compound, mathematical modelling is used to quantify absorption and elimination rates from internal exposure over time profiles after waterborne treatment, as well as changes in these parameters in post-hatching larvae of 3, 4, and 5 days post fertilisation (dpf). An increase of 106% in absorption rate was observed between 3 and 4 dpf, but no further increase at 5 dpf, and an increase of 17.5% in elimination rate for each dpf. Paracetamol clearance, determined from elimination rate constants and reported total larval volumes of 253, 263, and 300 nL at 3, 4, and 5 dpf respectively, correlates best with higher vertebrates at 5 dpf. This suggests that when studying direct effects of exogenous compounds, experiments with zebrafish larvae are best performed at 5 dpf.

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          The zebrafish reference genome sequence and its relationship to the human genome.

          Zebrafish have become a popular organism for the study of vertebrate gene function. The virtually transparent embryos of this species, and the ability to accelerate genetic studies by gene knockdown or overexpression, have led to the widespread use of zebrafish in the detailed investigation of vertebrate gene function and increasingly, the study of human genetic disease. However, for effective modelling of human genetic disease it is important to understand the extent to which zebrafish genes and gene structures are related to orthologous human genes. To examine this, we generated a high-quality sequence assembly of the zebrafish genome, made up of an overlapping set of completely sequenced large-insert clones that were ordered and oriented using a high-resolution high-density meiotic map. Detailed automatic and manual annotation provides evidence of more than 26,000 protein-coding genes, the largest gene set of any vertebrate so far sequenced. Comparison to the human reference genome shows that approximately 70% of human genes have at least one obvious zebrafish orthologue. In addition, the high quality of this genome assembly provides a clearer understanding of key genomic features such as a unique repeat content, a scarcity of pseudogenes, an enrichment of zebrafish-specific genes on chromosome 4 and chromosomal regions that influence sex determination.
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            Piraña and PCluster: a modeling environment and cluster infrastructure for NONMEM.

            Pharmacokinetic-pharmacodynamic modeling using non-linear mixed effects modeling (NONMEM) is a powerful yet challenging technique, as the software is generally accessed from the command line. A graphical user interface, Piraña, was developed that offers a complete modeling environment for NONMEM, enabling both novice and advanced users to increase efficiency of their workflow. Piraña provides features for the management and creation of model files, the overview of modeling results, creation of run reports and handling of datasets and output tables, and the running of custom R scripts on model output. Through the secure shell (SSH) protocol, Piraña can also be used to connect to Linux clusters (SGE, MOSIX) for distribution of workload. Modeling with NONMEM is computationally burdensome, which may be alleviated by distributing runs to computer clusters. A solution to this problem is offered here, called PCluster. This platform is easy to set up, runs in standard network environments, and can be extended with additional nodes if needed. The cluster supports the modeling toolkit Perl speaks NONMEM (PsN), and can include dedicated or non-dedicated PCs. A daemon script, written in Perl, was designed to run in the background on each node in the cluster, and to manage job distribution. The PCluster can be accessed from Piraña, and both software products have extensively been tested on a large academic network. The software is available under an open-source license. 2011 Elsevier Ireland Ltd. All rights reserved.
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              Systematic approaches to toxicology in the zebrafish.

              As the current paradigms of drug discovery evolve, it has become clear that a more comprehensive understanding of the interactions between small molecules and organismal biology will be vital. The zebrafish is emerging as a complement to existing in vitro technologies and established preclinical in vivo models that can be scaled for high-throughput. In this review, we highlight the current status of zebrafish toxicology studies, identify potential future niches for the model in the drug development pipeline, and define the hurdles that must be overcome as zebrafish technologies are refined for systematic toxicology.
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                Author and article information

                Contributors
                h.p.spaink@biology.leidenuniv.nl
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                15 February 2019
                15 February 2019
                2019
                : 9
                : 2149
                Affiliations
                [1 ]ISNI 0000 0001 2312 1970, GRID grid.5132.5, Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research (LACDR), , Leiden University, ; Leiden, The Netherlands
                [2 ]Certara QSP, Canterbury Innovation House, Canterbury, UK
                [3 ]ISNI 0000 0001 2312 1970, GRID grid.5132.5, Animal Sciences and Health, Institute of Biology Leiden (IBL), , Leiden University, ; Leiden, The Netherlands
                Author information
                http://orcid.org/0000-0001-7247-1360
                http://orcid.org/0000-0001-6006-1567
                http://orcid.org/0000-0001-8541-0882
                http://orcid.org/0000-0002-2931-4295
                http://orcid.org/0000-0001-7871-2073
                http://orcid.org/0000-0003-4128-9501
                Article
                38530
                10.1038/s41598-019-38530-w
                6377609
                30770889
                461becc9-3e01-46a5-8c13-c6d3ef59dc85
                © The Author(s) 2019

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 17 September 2018
                : 18 December 2018
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