Gut microbiota in the pharmacokinetics and colonic deglycosylation metabolism of ginsenoside Rb1 in rats: Contrary effects of antimicrobials treatment and restraint stress

Ginsenoside Rb-1, an active ingredient in Panax ginseng, was widely used for its various biological activities. To clarify the role of the gut microbiota in pharmacokinetics and metabolism of Rb-1, a comprehensive and comparative study of colonic deglycosylation metabolism and systemic exposure of ginsenoside Rb-1 in normal rats, antimicrobials (ATMs) treated rats, and restraint stressed rats was conducted. ATMs treated rats received oral administration of non-absorbable antimicrobial mixtures for 7 consecutive days. Restraint stressed rats were subjected to repeated restraint stress for a period of 2 h once daily for 7 days. Plasma concentration dynamics, urine and fecal excretion of Rb-1 and its deglycosylation metabolites (Rd, F-2, and C-K) were studied. Moreover, the in vitro metabolism of Rb-1 in fecal suspension and the fecal beta-D-glucosidase activity were profiled. Systemic exposure of the deglycosylation metabolites of ginsenoside Rb-1 (F-2, C-K) were significantly higher in restraint stressed rats, but ATMs treated rats exhibited a decreased plasma levels of F-2 and C-K, compared with normal rats. Further studies illustrated that altered systemic Rb-1 and its deglycosylation metabolites exposure in restraint-stressed rats and ATMs treated rats may be partially attributed to alternations in cumulative fecal excretion. The distinguishing fecal beta-D-glucosidase, in vitro elimination of Rb-1, and formation of these deglycosylation metabolites afforded further evidence for the in vivo data. In conclusion, the dysregulated fecal beta-D-glucosidase activity and deglycosylation metabolism may contribute to the altered pharmacokinetic of ginsenoside Rb-1 and its hydrolysis metabolites after ATMs treatment or restraint stress exposure. Our results may offer valuable insights into the pharmacological changes of bioactive ginsenosides in dys-regulated gut microbiota statue. (C) 2016 Elsevier Ireland Ltd. All rights reserved.