Successful dosing in zebrafish calls for an understanding of translational pharmacology

Clinical performance of drugs developed in zebrafish has proven the animal reliable to understand drug-dose outcomes. However, while traditional translational dosing in zebrafish has been widely calculated based on body weight normalization; accurate translational dosing also depends on an understanding of substrate depletion and production of their metabolites with a similarity to that of humans. We would suggest a metabolic stability testing requirement for each candidate to be tested. While that might be the best by standards; however, another simpler method is that during early screening stages, zebrafish models that are employed, could be evaluated for metabolic parallels by evaluating known drug concentration responses for similar class of molecules to that of the candidates under investigation. Deviations could be noted and accurate translational dosing can be calculated to generate a sharp resolution of candidates during further development of the candidates.

Zebrafish has already been proven to have a high degree of conservation of both phase I and phase II drug metabolic enzymes with humans.

In one study paracetamol pharmacokinetics in zebrafish indicated a high level of correlation of absolute clearance and distribution volume with higher vertebrates. Similarly, in another case a total of ten calycosin metabolites were detected to undergo glucuronidation, glucosylation, sulfation, oxidation, or a combination of two of these metabolisms, concluding that phase II conjugation of calycosin in zebrafish and mammalian systems correlated well. Also, combined transcriptomics and proteomics indicates a high degree of conservation of both phase I and phase II drug metabolic enzymes between zebrafish larvae and mammals.

For a successful translational use of zebrafish data, a metabolite stability test would enable a sharper translational prowess for further development and would also be an excellent method to identify optimal administration route.

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