Background and Objectives: As a natural analog of cannabidiol (CBD), nonpsychoactive cannabidivarin (CBDV) has therapeutic potential. However, the precise metabolism of CBDV either in vivo or in vitro has not been fully understood. Objective and Experimental Approach: Therefore, mice were intragastrically administered CBDV, and metabolite-rich and potential target organs and tissues were collected and analyzed by ultrahigh-performance liquid chromatography-quadrupole time-of-flight mass spectrometry. The metabolic pathways of CBDV in mice were illustrated more comprehensively for the first time. Results: Twenty-one metabolites were found, all of which, except decarbonylated CBDV, were initially identified. Compared with CBD, the newly identified metabolic pathways were single dehydrogenation, combined decarbonylation and monohydroxylation, and glutathione conjugations of CBDV and its phase I metabolite. Conclusions: According to the very low response in plasma and the extremely high response in intestinal contents 1 h later after the administration, it was assumed that the oral bioavailability of CBDV was as poor as that of CBD, and the major forms to excrete were conjugates of glutathione and glucuronic acid. In contrast to CBDV, decarbonylated CBDV in the keto form and enol form had considerable responses in plasma and preferred to target fatty tissues and organs owing to their higher lipophilicity. Whether these forms can function as genuine active substances in vivo instead of CBDV is worthy of investigation. These results and supposes contribute notable information regarding the pharmacokinetics and pharmacodynamics of CBDV.
Keywords: cannabidivarin; intestinal contents; metabolites; organs; plasma.