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In this study, in vivo metabolic studies of the synthetic cannabinoid 4F-MDMB-BICA were investigated using zebrafish models. The metabolites were identified and structurally illustrated by liquid chromatography-high resolution mass spectrometry.Fourteen phase-I metabolites and four phase-II metabolites were generated from zebrafish. The main metabolic pathways of the phase-I metabolism included N-dealkylation, N-dealkylation combined with hydroxylation, amide hydrolysis, oxidative defluorination, oxidative defluorination to butyric acid, acetic acid formation at the indole side chain, hydroxylation, ester hydrolysis followed by hydroxylation, dehydrogenation, dehydrogenation, and N-dealkylation, and oxidative defluorination subsequently combined with dehydrogenation. The main biotransformations of the phase-II metabolism were glucuronidation and sulfation. Two phase-I metabolites (A1 and A11) and four phase-II metabolites (A2, A3, A4, and A12) were reported for the first time. A14, which was confirmed in human biological samples, was detected only in zebrafish samples but not found in human liver microsome incubation study.The current study indicates that the zebrafish model is a promising tool for elucidating the metabolism of NPS in the future.

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