Pharmacokinetic Modeling of Paracetamol Uptake and Clearance in Zebrafish Larvae: Expanding the Allometric Scale in Vertebrates with Five Orders of Magnitude
| العنوان: | Pharmacokinetic Modeling of Paracetamol Uptake and Clearance in Zebrafish Larvae: Expanding the Allometric Scale in Vertebrates with Five Orders of Magnitude |
|---|---|
| المؤلفون: | Vasudev Kantae, Anita Ordas, Elke H. J. Krekels, Peter Racz, Rob C. van Wijk, Piet H. van der Graaf, Oskar González, Herman P. Spaink, Thomas Hankemeier, Amy C. Harms |
| المصدر: | Zebrafish Zebrafish, 2016 |
| سنة النشر: | 2016 |
| مصطلحات موضوعية: | 0301 basic medicine, Drug, animal structures, paracetamol, media_common.quotation_subject, Drug Evaluation, Preclinical, Danio, Pharmacology, Mass Spectrometry, drug discovery, 03 medical and health sciences, 0302 clinical medicine, Pharmacokinetics, allometry, Zebrafish larvae, medicine, Animals, Zebrafish, Acetaminophen, media_common, biology, digestive, oral, and skin physiology, fungi, Analgesics, Non-Narcotic, Models, Theoretical, zebrafish, biology.organism_classification, Research Papers, Orders of magnitude (mass), 030104 developmental biology, Nonlinear Dynamics, 030220 oncology & carcinogenesis, Animal Science and Zoology, Allometry, pharmacokinetics, metabolism, Chromatography, Liquid, Developmental Biology, medicine.drug |
| الوصف: | 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. |
| اللغة: | English |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::4031c803bf2fa6dd49feb918fc64c244 https://hdl.handle.net/1887/43746 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....4031c803bf2fa6dd49feb918fc64c244 |
| قاعدة البيانات: | OpenAIRE |
| الوصف غير متاح. |