Abstract
Zebrafish (Danio rerio) is increasingly used to assess the pharmacological activity and toxicity of compounds. The spatiotemporal distribution of seven fluorescent alkyne compounds was examined during 48 h after immersion (10 µM) or microinjection (2 mg/kg) in the pericardial cavity (PC), intraperitoneally (IP) and yolk sac (IY) of 3 dpf zebrafish eleuthero-embryos. By modelling the fluorescence of whole-body contours present in fluorescence images, the main pharmacokinetic (PK) parameter values of the compounds were determined. It was demonstrated that especially in case of short incubations (1–3 h) immersion can result in limited intrabody exposure to compounds. In this case, PC and IP microinjections represent excellent alternatives. Significantly, IY microinjections did not result in a suitable intrabody distribution of the compounds. Performing a QSPkR (quantitative structure-pharmacokinetic relationship) analysis, LogD was identified as the only molecular descriptor that explains the final uptake of the selected compounds. It was also shown that combined administration of compounds (immersion and microinjection) provides a more stable intrabody exposure, at least in case of a prolonged immersion and compounds with LogD value > 1. These results will help reduce the risk of false negative results and can offer an invaluable input for future translational research and safety assessment applications.
Highlights
Zebrafish (Danio rerio) is increasingly used to assess the pharmacological activity and toxicity of compounds
There is a risk for compounds to be identified as false negatives due to incomplete metabolism
We used SwissADME to compute a selection of molecular descriptors of seven fluorescent compounds, i.e., molecular weight (MW), polar surface area (TPSA), molar refractivity (MR) and number of H-bond acceptors (HBA), H-bond donors (HBD) and rotatable bonds
Summary
Zebrafish (Danio rerio) is increasingly used to assess the pharmacological activity and toxicity of compounds. It was shown that combined administration of compounds (immersion and microinjection) provides a more stable intrabody exposure, at least in case of a prolonged immersion and compounds with LogD value > 1 These results will help reduce the risk of false negative results and can offer an invaluable input for future translational research and safety assessment applications. Protocols have been established that allow zebrafish eleuthero-embryos to be exposed to compounds after prior in vitro metabolism by rat liver m icrosomes[15,16] Another limitation is the low uptake of compounds by zebrafish after immersion exposure, the most common administration route used in toxicity screens, possibly resulting in false negative o utcomes[5,14,17,18]. A detailed comparison with results obtained after immersion using the same compounds is completely lacking
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