DDMODEL00000294: Executable_Paracetamol_Zebrafish_345dpf

  public model
Short description:
Paracetamol pharmacokinetics in zebrafish larvae of 3, 4, and 5 dpf including age as covariate on absorption and elimination.
Original code
  • Impact of post-hatching maturation on the pharmacokinetics of paracetamol in zebrafish larvae
  • Rob C van Wijk
  • Scientific Reports, 2/2019, Volume 9, pages: 2149
  • Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands, Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Leiden, The Netherlands, Animal Sciences and Health, Ins
  • 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.
Rob Christiaan van Wijk
Context of model development: Variability sources in PK and PD (CYP, Renal, Biomarkers);
Long technical model description: Zebrafish larvae of 3, 4, and 5 dpf have been treated with 1 mM paracetamol in surrounding medium for designated times after which internal exposure is quantified in homogenates (destructive sampling). Model identifies age as covariate on absorption (discrete, changed between 3 and 4 dpf) and on elimination (power relation, 17.5% increased elimination per day post fertilisation). Error model is combination of additive and proportional. ;
Model compliance with original publication: Yes;
Model implementation requiring submitter’s additional knowledge: No;
Modelling context description: Impact of age on absorption and elimination of paracetamol by zebrafish larvae;
Modelling task in scope: estimation;
Nature of research: Fundamental/Basic research;
Annotations are correct.
This model is not certified.
  • Model owner: Rob Christiaan van Wijk
  • Submitted: Jan 4, 2019 8:53:51 AM
  • Last Modified: Jan 4, 2019 8:53:51 AM
  • Version: 12 public model Download this version
    • Submitted on: Jan 4, 2019 8:53:51 AM
    • Submitted by: Rob Christiaan van Wijk
    • With comment: Model revised without commit message