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Evaluation of the Percutaneous Absorption of Drug Molecules in Zebrafish
Article

Drug Administration Routes Impact the Metabolism of a Synthetic Cannabinoid in the Zebrafish Larvae Model

1
Department of Microbial Natural Products, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI) and Department of Pharmacy, Saarland University, Campus E8 1, 66123 Saarbrücken, Germany
2
Environmental Safety Group, Korea Institute of Science and Technology (KIST) Europe, 66123 Saarbrücken, Germany
3
Department of Experimental and Clinical Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Center for Molecular Signaling (PZMS), Saarland University, 66421 Homburg, Germany
4
German Center for Infection Research (DZIF), Partner Site Hannover-Braunschweig Germany, 38124 Braunschweig, Germany
*
Authors to whom correspondence should be addressed.
Academic Editors: Yasuhito Shimada and Herman P. Spaink
Molecules 2020, 25(19), 4474; https://doi.org/10.3390/molecules25194474
Received: 8 September 2020 / Revised: 24 September 2020 / Accepted: 27 September 2020 / Published: 29 September 2020
(This article belongs to the Special Issue Zebrafish-Based Drug Screening)
Zebrafish (Danio rerio) larvae have gained attention as a valid model to study in vivo drug metabolism and to predict human metabolism. The microinjection of compounds, oligonucleotides, or pathogens into zebrafish embryos at an early developmental stage is a well-established technique. Here, we investigated the metabolism of zebrafish larvae after microinjection of methyl 2-(1-(5-fluoropentyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamido)-3,3-dimethylbutanoate (7′N-5F-ADB) as a representative of recently introduced synthetic cannabinoids. Results were compared to human urine data and data from the in vitro HepaRG model and the metabolic pathway of 7′N-5F-ADB were reconstructed. Out of 27 metabolites detected in human urine samples, 19 and 15 metabolites were present in zebrafish larvae and HepaRG cells, respectively. The route of administration to zebrafish larvae had a major impact and we found a high number of metabolites when 7′N-5F-ADB was microinjected into the caudal vein, heart ventricle, or hindbrain. We further studied the spatial distribution of the parent compound and its metabolites by mass spectrometry imaging (MSI) of treated zebrafish larvae to demonstrate the discrepancy in metabolite profiles among larvae exposed through different administration routes. In conclusion, zebrafish larvae represent a superb model for studying drug metabolism, and when combined with MSI, the optimal administration route can be determined based on in vivo drug distribution. View Full-Text
Keywords: zebrafish larvae model; metabolism; administration route; microinjection; HepaRG cells; mass spectrometry imaging (MSI); synthetic cannabinoid; methyl 2-(1-(5-fluoropentyl)-1H-pyrrolo [2,3-b]pyridine-3-carboxamido)-3,3-dimethylbutanoate (7′N-5F-ADB); 3R principle; drug metabolism and pharmacokinetics (DMPK) zebrafish larvae model; metabolism; administration route; microinjection; HepaRG cells; mass spectrometry imaging (MSI); synthetic cannabinoid; methyl 2-(1-(5-fluoropentyl)-1H-pyrrolo [2,3-b]pyridine-3-carboxamido)-3,3-dimethylbutanoate (7′N-5F-ADB); 3R principle; drug metabolism and pharmacokinetics (DMPK)
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MDPI and ACS Style

Park, Y.M.; Meyer, M.R.; Müller, R.; Herrmann, J. Drug Administration Routes Impact the Metabolism of a Synthetic Cannabinoid in the Zebrafish Larvae Model. Molecules 2020, 25, 4474. https://doi.org/10.3390/molecules25194474

AMA Style

Park YM, Meyer MR, Müller R, Herrmann J. Drug Administration Routes Impact the Metabolism of a Synthetic Cannabinoid in the Zebrafish Larvae Model. Molecules. 2020; 25(19):4474. https://doi.org/10.3390/molecules25194474

Chicago/Turabian Style

Park, Yu M., Markus R. Meyer, Rolf Müller, and Jennifer Herrmann. 2020. "Drug Administration Routes Impact the Metabolism of a Synthetic Cannabinoid in the Zebrafish Larvae Model" Molecules 25, no. 19: 4474. https://doi.org/10.3390/molecules25194474

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