Drug Administration Routes Impact the Metabolism of a Synthetic Cannabinoid in the Zebrafish Larvae Model
Zebrafish (<i>Danio rerio</i>) 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 tech...
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| Format: | Article |
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MDPI AG
2020-09-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/25/19/4474 |
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| author | Yu Mi Park Markus R. Meyer Rolf Müller Jennifer Herrmann |
| author_facet | Yu Mi Park Markus R. Meyer Rolf Müller Jennifer Herrmann |
| author_sort | Yu Mi Park |
| collection | DOAJ |
| description | Zebrafish (<i>Danio rerio</i>) 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)-1<i>H</i>-pyrrolo[2,3-b]pyridine-3-carboxamido)-3,3-dimethylbutanoate (7′<i>N</i>-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′<i>N</i>-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′<i>N</i>-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. |
| first_indexed | 2024-03-10T15:58:19Z |
| format | Article |
| id | doaj.art-e0fccef40dd240998264e93cb389a1ad |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T15:58:19Z |
| publishDate | 2020-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-e0fccef40dd240998264e93cb389a1ad2023-11-20T15:30:07ZengMDPI AGMolecules1420-30492020-09-012519447410.3390/molecules25194474Drug Administration Routes Impact the Metabolism of a Synthetic Cannabinoid in the Zebrafish Larvae ModelYu Mi Park0Markus R. Meyer1Rolf Müller2Jennifer Herrmann3Department 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, GermanyDepartment of Experimental and Clinical Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Center for Molecular Signaling (PZMS), Saarland University, 66421 Homburg, GermanyDepartment 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, GermanyDepartment 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, GermanyZebrafish (<i>Danio rerio</i>) 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)-1<i>H</i>-pyrrolo[2,3-b]pyridine-3-carboxamido)-3,3-dimethylbutanoate (7′<i>N</i>-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′<i>N</i>-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′<i>N</i>-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.https://www.mdpi.com/1420-3049/25/19/4474zebrafish larvae modelmetabolismadministration routemicroinjectionHepaRG cellsmass spectrometry imaging (MSI) |
| spellingShingle | Yu Mi Park Markus R. Meyer Rolf Müller Jennifer Herrmann Drug Administration Routes Impact the Metabolism of a Synthetic Cannabinoid in the Zebrafish Larvae Model Molecules zebrafish larvae model metabolism administration route microinjection HepaRG cells mass spectrometry imaging (MSI) |
| title | Drug Administration Routes Impact the Metabolism of a Synthetic Cannabinoid in the Zebrafish Larvae Model |
| title_full | Drug Administration Routes Impact the Metabolism of a Synthetic Cannabinoid in the Zebrafish Larvae Model |
| title_fullStr | Drug Administration Routes Impact the Metabolism of a Synthetic Cannabinoid in the Zebrafish Larvae Model |
| title_full_unstemmed | Drug Administration Routes Impact the Metabolism of a Synthetic Cannabinoid in the Zebrafish Larvae Model |
| title_short | Drug Administration Routes Impact the Metabolism of a Synthetic Cannabinoid in the Zebrafish Larvae Model |
| title_sort | drug administration routes impact the metabolism of a synthetic cannabinoid in the zebrafish larvae model |
| topic | zebrafish larvae model metabolism administration route microinjection HepaRG cells mass spectrometry imaging (MSI) |
| url | https://www.mdpi.com/1420-3049/25/19/4474 |
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