title: Pharmacokinetic alterations of rhubarb anthraquinones in experimental colitis induced by dextran sulfate sodium in the rat.
abstract: BACKGROUND
  Rhubarb (Rhei Rhizoma et Radix) is used for the treatment of digestive diseases in traditional medicinal practice in China. Recent studies also support its beneficial activities in alleviating ulcerative colitis (UC).
  
  
  OBJECTIVE
  This study aimed to characterize the oral pharmacokinetics of rhubarb anthraquinones, the main bioactive components of this herb, in the experimental chronic colitis rat model induced by dextran sulfate sodium (DSS) and to identify the factors causing the pharmacokinetic alterations.
  
  
  METHODS
  Rats received drinking water (normal group) or 5% DSS for the first 7 days and 3% DSS for additional 14 days (UC group). On day 21 both groups received an oral dose of the rhubarb extract (equivalent to 5.0g crude drug/kg body weight). Plasma anthraquinone aglycones levels were determined directly by an LC-MS/MS method and the total of each anthraquinone (aglycone+conjugates) was quantified after β-glucuronidases hydrolysis.
  
  
  RESULTS
  Rhubarb anthraquinones predominantly existed as conjugates in plasma samples from both groups and only free aloe-emodin, rhein and emodin were detected. Compared to the normal rats, both Cmaxand AUC of the three free anthraquinones were increased, while the systemic exposure (AUC) of the total (aglycone+conjugates) of most anthraquinones decreased by UC accompanied by the disappearance of multiple-peak phenomenon in the plasma concentration-time profiles. Gut bacteria from UC rats exhibited a decreased activity in hydrolyzing anthraquinone glycosides to form respective aglycone and there were significant decreases in microbial β-glucosidases and β-glucuronidases activities. Moreover, the intestinal microsomes from UC rats catalyzed glucuronidation of free anthraquinones with higher activities, while the activities of hepatic microsomes were comparable to normal rats.
  
  
  CONCLUSIONS
  The decreases of β-glucuronidases activity in DSS-induced chronic rat colitis should mainly account for the decreases in systemic exposure and abrogation of enterohepatic recirculation of most rhubarb anthraquinones after oral intake.
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China.
authors.forename: Wen-Jin
authors.initials: WJ
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China.
authors.forename: Ru
authors.initials: R
authors.lastname: Yan
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Li
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China.
authors.forename: Ya-Ping
authors.initials: YP
authors.lastname: Li
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China.
authors.forename: Rui-Na
authors.initials: RN
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China.
authors.forename: Yi-Tao
authors.initials: YT
authors.lastname: Wang
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000880:Anthraquinones / Q000008:administration & dosage / Q000302:isolation & purification / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002853:Chromatography, Liquid; D003093:Colitis, Ulcerative / Q000503:physiopathology*; D016264:Dextran Sulfate / Q000633:toxicity; D004195:Disease Models, Animal; D005966:Glucuronidase / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D008297:Male; D008516:Medicine, Chinese Traditional; D008861:Microsomes / Q000378:metabolism; D008862:Microsomes, Liver / Q000378:metabolism; D010936:Plant Extracts / Q000008:administration & dosage / Q000493:pharmacokinetics*; D018517:Plant Roots; D051381:Rats; D017207:Rats, Sprague-Dawley; D012250:Rheum / Q000737:chemistry*; D027343:Rhizome; D053719:Tandem Mass Spectrometry
chemical_list: D000880:Anthraquinones; D010936:Plant Extracts; D016264:Dextran Sulfate; D005966:Glucuronidase