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Pharmacokinetic Modeling of Paracetamol Uptake and Clearance in Zebrafish Larvae: Expanding the Allometric Scale in Vertebrates with Five Orders of Magnitude
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....
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Mary Ann Liebert, Inc.
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5124745/ https://www.ncbi.nlm.nih.gov/pubmed/27632065 http://dx.doi.org/10.1089/zeb.2016.1313 |
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author | Kantae, Vasudev Krekels, Elke H.J. Ordas, Anita González, Oskar van Wijk, Rob C. Harms, Amy C. Racz, Peter I. van der Graaf, Piet H. Spaink, Herman P. Hankemeier, Thomas |
author_facet | Kantae, Vasudev Krekels, Elke H.J. Ordas, Anita González, Oskar van Wijk, Rob C. Harms, Amy C. Racz, Peter I. van der Graaf, Piet H. Spaink, Herman P. Hankemeier, Thomas |
author_sort | Kantae, Vasudev |
collection | PubMed |
description | 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 × 10(7) 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. |
format | Online Article Text |
id | pubmed-5124745 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Mary Ann Liebert, Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-51247452016-12-07 Pharmacokinetic Modeling of Paracetamol Uptake and Clearance in Zebrafish Larvae: Expanding the Allometric Scale in Vertebrates with Five Orders of Magnitude Kantae, Vasudev Krekels, Elke H.J. Ordas, Anita González, Oskar van Wijk, Rob C. Harms, Amy C. Racz, Peter I. van der Graaf, Piet H. Spaink, Herman P. Hankemeier, Thomas Zebrafish Research Papers 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 × 10(7) 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. Mary Ann Liebert, Inc. 2016-12-01 2016-12-01 /pmc/articles/PMC5124745/ /pubmed/27632065 http://dx.doi.org/10.1089/zeb.2016.1313 Text en © Vasudev Kantae, et al., 2016; Published by Mary Ann Liebert, Inc. This Open Access article is distributed under the terms of the Creative Commons License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. |
spellingShingle | Research Papers Kantae, Vasudev Krekels, Elke H.J. Ordas, Anita González, Oskar van Wijk, Rob C. Harms, Amy C. Racz, Peter I. van der Graaf, Piet H. Spaink, Herman P. Hankemeier, Thomas Pharmacokinetic Modeling of Paracetamol Uptake and Clearance in Zebrafish Larvae: Expanding the Allometric Scale in Vertebrates with Five Orders of Magnitude |
title | Pharmacokinetic Modeling of Paracetamol Uptake and Clearance in Zebrafish Larvae: Expanding the Allometric Scale in Vertebrates with Five Orders of Magnitude |
title_full | Pharmacokinetic Modeling of Paracetamol Uptake and Clearance in Zebrafish Larvae: Expanding the Allometric Scale in Vertebrates with Five Orders of Magnitude |
title_fullStr | Pharmacokinetic Modeling of Paracetamol Uptake and Clearance in Zebrafish Larvae: Expanding the Allometric Scale in Vertebrates with Five Orders of Magnitude |
title_full_unstemmed | Pharmacokinetic Modeling of Paracetamol Uptake and Clearance in Zebrafish Larvae: Expanding the Allometric Scale in Vertebrates with Five Orders of Magnitude |
title_short | Pharmacokinetic Modeling of Paracetamol Uptake and Clearance in Zebrafish Larvae: Expanding the Allometric Scale in Vertebrates with Five Orders of Magnitude |
title_sort | pharmacokinetic modeling of paracetamol uptake and clearance in zebrafish larvae: expanding the allometric scale in vertebrates with five orders of magnitude |
topic | Research Papers |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5124745/ https://www.ncbi.nlm.nih.gov/pubmed/27632065 http://dx.doi.org/10.1089/zeb.2016.1313 |
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