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DDMODEL00000300: Nanoscale PK of paracetamol and metabolites in zebrafish larvae

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Short description:
Pharmacokinetics of paracetamol and its major metabolites paracetamol-glucuronide and paracetamol-sulphate in zebrafish larvae of 5 days post fertilization, based on blood samples as well as homogenates and medium.
Original code
  • Mechanistic and quantitative understanding of pharmacokinetics in zebrafish larvae through nanoscale blood sampling and metabolite modelling of paracetamol
  • Rob C van Wijk, Elke HJ Krekels, Vasudev Kantae, Anita Ordas, Thijs Kreling, Amy C Harms, Thomas Hankemeier, Herman P Spaink, Piet Hein van der Graaf
  • Journal of Pharmacology and Experimental Therapeutics, 8/2019
  • Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands: RCvW, EHJK, VK, TK, ACH, TH, PHvdG; Animal Sciences and Health, Institute of Biology Leiden, Leiden University, The Netherlands:
  • Zebrafish larvae are increasingly used for pharmacological research, but internal drug exposure is often not measured. Understanding pharmacokinetics is necessary for reliable translation of pharmacological results to higher vertebrates, including humans. Quantification of drug clearance and distribution requires measurements of blood concentrations. Additionally, measuring drug metabolites is of importance to understand clearance in this model organism mechanistically. We therefore mechanistically study and quantify pharmacokinetics in zebrafish larvae, and compare this to higher vertebrates, using paracetamol (acetaminophen) as paradigm compound. A method was developed to sample blood from zebrafish larvae at five days post fertilization. Blood concentrations of paracetamol and its major metabolites, paracetamol-glucuronide and paracetamol-sulphate, were measured. Blood concentration data were combined with measured amounts in larval homogenates and excreted amounts and simultaneously analysed through non-linear mixed effects modelling, quantifying absolute clearance and distribution volume. Blood sampling from zebrafish larvae was most successful from the posterior cardinal vein with median volume (interquartile range) of 1.12 (0.676-1.66) nL per blood sample. Samples were pooled (n=15-35) to reach measurable levels. Paracetamol blood concentrations at steady state were only 10% of the external paracetamol concentration. Paracetamol-sulphate was the major metabolite and its formation was quantified using a time-dependent metabolic formation rate. Absolute clearance and distribution volume correlated well to reported values in higher vertebrates, including humans. Based on blood concentrations and advanced data analysis, the mechanistic and quantitative understanding of paracetamol pharmacokinetics in zebrafish larvae has been established. This will improve the translational value of this vertebrate model organism in drug discovery and development.
Rob Christiaan van Wijk
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  • Model owner: Rob Christiaan van Wijk
  • Submitted: Jul 31, 2019 4:25:49 PM
  • Last Modified: Aug 5, 2019 4:48:35 PM
  • Version: 19 public model Download this version
    • Submitted on: Aug 5, 2019 4:48:35 PM
    • Submitted by: Rob Christiaan van Wijk
    • With comment: Edited model metadata online.
  • Version: 17 public model Download this version
    • Submitted on: Jul 31, 2019 4:25:49 PM
    • Submitted by: Rob Christiaan van Wijk
    • With comment: Edited model metadata online.