Enterogastric and enterohepatic recycling of dendrobine in rats: a novel disposition mechanism responsible for pharmacokinetic multiple peaks.

Dendrobine, a neuroprotective alkaloid, exhibited complex pharmacokinetics characterized by multiple peaks and continuous concentration plateaus in rats, particularly for dendrobine and its major metabolite N-demethylated dendrobine (N-deM dendrobine), but not for dendrobine N-oxide. This study elucidated the disposition mechanism underlying the multiple peaks phenomena through systematic investigation of tissue distribution, excretion, enteral reabsorption, and intestinal biotransformation. Key findings revealed that glucuronide N-deM dendrobine and glucuronide N-deM dendrobine N-oxide were major biliary metabolites, undergoing deglucuronidation and reduction in the jejunum to regenerate N-deM dendrobine for intestinal reabsorption. Interestingly, substantial quantities of dendrobine and its N-oxide were secreted into the gastric lumen through ion trapping, with dendrobine N-oxide functioning as a temporary storage form that underwent retro-reduction to dendrobine, facilitating subsequent intestinal reabsorption. The reabsorbed dendrobine was predominantly metabolized in the liver, yielding N-deM dendrobine and its glucuronide conjugates, dendrobine N-oxide, along with other metabolites, thereby facilitating enterohepatic recycling. In contrast, the reabsorbed N-deM dendrobine was primarily distributed into systemic circulation. Antibiotic-induced inhibition of intestinal biotransformation partially abolished the multiple peaks, suggesting that gut microbiota significantly influenced the pharmacokinetics of dendrobine and its metabolites. In conclusion, dendrobine and dendrobine N-oxide abundantly underwent gastric secretion-enteral reduction-reabsorption, resulting in multiple peaks of dendrobine. The reabsorbed dendrobine also supported the enterohepatic recycling of N-deM dendrobine through hepatic metabolism, driving its pharmacokinetic multiple peaks. The enterohepatic recycling of glucuronide metabolites of N-deM dendrobine was partially responsible for multiple peaks of N-deM dendrobine.