Comprehensive pharmacokinetic analysis of trans-crocetin and its metabolites- cis-crocetin, CM, and CD- in rats using...

Crocetin, an active component of saffron (Crocus sativus L.), exhibits antidepressant, anti-tumor, and anti-diabetic effects. However, the pharmacokinetics of trans-crocetin and its metabolites, such as cis-crocetin, crocetin-monoglucuronide (CM), and crocetin-diglucuronide (CD), after intragastric (i.g.) administration of trans-crocetin in vivo remains underexplored. In the present study, a sensitive and reliable UPLC-Q-Orbitrap-MS/MS method was developed to comprehensively elucidate the preclinical pharmacokinetic patterns of trans-crocetin and the distribution characteristics of its metabolites in rats for the first time. The established UPLC-Q-Orbitrap-MS/MS method has good specificity and selectivity, with the accuracy, precision, recovery, and matrix effect meeting the methodological requirements. Pharmacokinetic analysis revealed rapid absorption of trans-crocetin into the blood, with a biphasic absorption pattern observed for trans-crocetin and CM. The absorbed trans/cis-crocetin were widely distributed in rat tissues, especially spleen, heart, adipose and lungs. Notably, trans/cis-crocetin and CM were detected simultaneously in rat brain tissue, indicating that crocetin can cross the blood-brain barrier. The CD was only detected in plasma and not in other tissues. The small intestine and liver appear to be key sites for the glucuronidation and conformational change of trans-crocetin, respectively. The elimination rates of trans/cis-crocetin and CM in tissues were significantly slower than in the blood. Trans-Crocetin was primarily excreted in feces and kidneys, while cis-crocetin and CM were cleared mainly by the kidneys. The pharmacokinetic process and tissue distribution characteristics of trans/cis-crocetin, CM, and CD were expounded in this study, which can provide a scientific basis and guidance for the further development and utilization of crocetin.