Orally administered crocin rapidly and efficiently rescues depressive-like behaviors in depression models; however, crocin levels in the circulatory and central nervous systems are rather low. The underlying mechanism responsible for the inconsistency between pharmacokinetics and pharmacodynamics is unknown. To identify the active metabolites and clarify the underlying mechanisms, the pharmacokinetics and metabolic effects of the gut flora and hepatic and intestinal microsomes on crocin were examined, and the pharmacodynamics of crocin and its major metabolite, crocetin, were also evaluated in both normal and pseudo germ-free mice subjected to chronic social defeat stress. The results showed that oral administration of 300 mg/kg crocin significantly improved the depression-like behaviors of chronic social defeat stress mice, although the levels of crocin in the circulatory system were rather low (Cmax = 43.5 ± 8.6 μg/L; AUC = 151 ± 20.8 μg·h/L). However, the primary metabolite of crocetin was much more abundant in vivo (Cmax = 4662.5 ± 586.1 μg/L; AUC = 33,451.9 ± 3323.6 μg·h/L). Orally administered crocin was primarily metabolized into crocetin by the gut flora instead of hepatic or intestinal microsomal enzymes, and less than 10% of crocin was transformed into crocetin in the liver or intestinal microsomes. Inhibition of the gut flora dramatically reduced the production of and in vivo exposure to crocetin, and the rapid antidepressant effect of crocin disappeared. Moreover, crocetin showed rapid antidepressant effects similar to those of crocin, and the effects were independent of the gut flora. In conclusion, the metabolic transformation of crocin to crocetin primarily contributes to the rapid antidepressant effects of crocin and is dependent on the gut flora.
