Gut microbiota in the pharmacokinetics and colonic deglycosylation metabolism of ginsenoside Rb1 in rats: Contrary effects of antimicrobials treatment and restraint stress.
Ginsenoside Rb1, 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 Rb1, a comprehensive and comparative study of colonic deglycosylation metabolism and systemic exposure of ginsenoside Rb1 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 Rb1 and its deglycosylation metabolites (Rd, F2, and C-K) were studied. Moreover, the in vitro metabolism of Rb1 in fecal suspension and the fecal β-d-glucosidase activity were profiled. Systemic exposure of the deglycosylation metabolites of ginsenoside Rb1 (F2, C-K) were significantly higher in restraint stressed rats, but ATMs treated rats exhibited a decreased plasma levels of F2 and C-K, compared with normal rats. Further studies illustrated that altered systemic Rb1 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 β-d-glucosidase, in vitro elimination of Rb1, and formation of these deglycosylation metabolites afforded further evidence for the in vivo data. In conclusion, the dys-regulated fecal β-d-glucosidase activity and deglycosylation metabolism may contribute to the altered pharmacokinetic of ginsenoside Rb1 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.
Jiangsu Key Laboratory of Pediatric Respiratory Disease, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, PR China; Jiangsu Provincial Traditional Chinese Medicine High Efficient Drug Delivery System Engineering Technology Research Center, Nanjing 210023, PR China. Electronic address: kanga@njucm.edu.cn.
An
A
Kang
Jiangsu Key Laboratory of Pediatric Respiratory Disease, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, PR China; Jiangsu Provincial Traditional Chinese Medicine High Efficient Drug Delivery System Engineering Technology Research Center, Nanjing 210023, PR China.
Shengjie
S
Zhang
Jiangsu Key Laboratory of Pediatric Respiratory Disease, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, PR China.
Dong
D
Zhu
Jiangsu Key Laboratory of Pediatric Respiratory Disease, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, PR China; Jiangsu Provincial Traditional Chinese Medicine High Efficient Drug Delivery System Engineering Technology Research Center, Nanjing 210023, PR China.
Yu
Y
Dong
Jiangsu Provincial Traditional Chinese Medicine High Efficient Drug Delivery System Engineering Technology Research Center, Nanjing 210023, PR China; Jiangsu Key Laboratory of Pediatric Respiratory Disease, Institute of Pediatrics, Nanjing University of Chinese Medicine, Nanjing 210023, PR China.
Jinjun
J
Shan
Jiangsu Key Laboratory of Pediatric Respiratory Disease, Institute of Pediatrics, Nanjing University of Chinese Medicine, Nanjing 210023, PR China.
Tong
T
Xie
Jiangsu Key Laboratory of Pediatric Respiratory Disease, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, PR China.
Hongmei
H
Wen
Jiangsu Key Laboratory of Pediatric Respiratory Disease, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, PR China; Jiangsu Provincial Traditional Chinese Medicine High Efficient Drug Delivery System Engineering Technology Research Center, Nanjing 210023, PR China. Electronic address: diliuqing@hotmail.com.
Liuqing
L
Di
D000284:Administration, Oral; D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects; D003106:Colon / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D064806:Dysbiosis; D005243:Feces / Q000737:chemistry; D000069196:Gastrointestinal Microbiome / Q000187:drug effects*; D036145:Ginsenosides / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics*; D006031:Glycosylation / Q000187:drug effects; D008297:Male; D055442:Metabolome / Q000187:drug effects; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results; D012149:Restraint, Physical; D013312:Stress, Physiological / Q000187:drug effects*; D001616:beta-Galactosidase / Q000378:metabolism
D000890:Anti-Infective Agents; D036145:Ginsenosides; C442759:ginsenoside Rb1; D001616:beta-Galactosidase
Antimicrobials treatment; Deglycosylation metabolism; Ginsenoside Rb(1); Microbiota; Pharmacokinetics; Restraint stress