Abstract
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.
Highlights
The zebrafish (Danio rerio), especially the zebrafish larva, is increasingly used in drug discovery and early drug development, and toxicological screens[1,2]
Because target engagement, which is responsible for the response to exogenous compounds, depends on the pharmacokinetics or toxicokinetics of internal exposure over time, longitudinal data of exposure over time is needed for reliable interpretation of observed effects[13,14,15]
The observed internal exposure of paracetamol expressed as total amount per larva over time is shown in Fig. 1 for larvae of 3, 4, and 5 dpf for both the constant waterborne treatment and the washout experiment
Summary
The zebrafish (Danio rerio), especially the zebrafish larva, is increasingly used in drug discovery and early drug development, and toxicological screens[1,2]. As most experiments in the field of pharmacology and toxicology are performed during these first days[1], it is essential to understand and quantify the impact of development, and to know what difference a single experimental day makes on the internal exposure of exogenous compounds. This is especially the case when studying direct, short-term effects of exogenous compounds
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