title: In vitro and in situ evaluation of herb-drug interactions during intestinal metabolism and absorption of baicalein.
abstract: BACKGROUND
  Baicalein (B), a bioactive flavone isolated from the root of a traditional Chinese medicinal herb Scutellaria baicalensis Georgi, was found to undergo extensive intestinal Phase II metabolism during its absorption process. Compounds sharing the same metabolic pathways with B or being inhibitors of enzymes UGT and SULT are expected to interfere with the metabolism of B leading to alteration of the absorption of B. The present study aims to identify potential intestinal absorption and metabolism interactions between B and four selected compounds, namely acetaminophen (APAP), (-)-epicatechin (EC), piperine (PIP) and curcumin (CUR) using in vitro and in situ models.
  
  
  METHODS
  Three in vitro and one in situ methods were employed to investigate the effect of selected compounds on the metabolism and absorption on B. Incubation studies using rat intestinal s9 and Caco-2 cell lysate were used to study the effect of selected compounds on glucuronidation and sulfation of B. Sigmoidal dose-response curves were plotted and IC(50) values were estimated. Apical to basolateral absorption study using Caco-2 cell monolayer model was also employed to study the effect of selected compounds on absorption of B. The most potent inhibitor identified was selected to further investigate its potential herb-drug interaction with B using in situ rat intestinal perfusion model. LC/MS/MS was used for the analysis of B and its metabolites in collected samples.
  
  
  RESULTS
  It was found that all the four selected compounds could produce a dose-dependent inhibition on the glucuronidation and sulfation of B. Moreover, the presence of CUR and high-dose EC demonstrated a subsequent increase in the absorption of B. In general, the order of potency on glucuronidation inhibition is: CUR>PIP>EC>APAP; while the potency order on sulfation inhibition is: CUR>EC>PIP>APAP. CUR was selected to further study its in vivo effect on B using in situ rat intestinal perfusion model. It was found that CUR could significantly increase the absorption of B via the inhibition on formation of its metabolites.
  
  
  CONCLUSIONS
  Our findings indicated that the intestinal metabolism of B could be inhibited by all the selected compounds with CUR being the most potent inhibitor, which could result in subsequent increase of absorption of B. The current study had significant implications for further investigation on the in vivo evaluations of the herb-drug and herb-herb interactions between B and selected compounds, especially CUR.
authors: School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong Special Administrative Region.
authors: Yui Kau
authors: YK
authors: Fong
authors: Chen Rui
authors: CR
authors: Li
authors: Siu Kwan
authors: SK
authors: Wo
authors: Shu
authors: S
authors: Wang
authors: Limin
authors: L
authors: Zhou
authors: Li
authors: L
authors: Zhang
authors: Ge
authors: G
authors: Lin
authors: Zhong
authors: Z
authors: Zuo
mesh_terms: D000082:Acetaminophen / Q000494:pharmacology; D000284:Administration, Oral; D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D052117:Benzodioxoles / Q000494:pharmacology; D001711:Biotransformation; D018938:Caco-2 Cells; D002392:Catechin / Q000494:pharmacology; D002853:Chromatography, Liquid; D003474:Curcumin / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004365:Drugs, Chinese Herbal / Q000008:administration & dosage / Q000493:pharmacokinetics*; D044950:Flavanones / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D020719:Glucuronides / Q000378:metabolism; D041743:Herb-Drug Interactions; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects; D007583:Jejunum / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008516:Medicine, Chinese Traditional; D010477:Perfusion; D010880:Piperidines / Q000494:pharmacology; D018517:Plant Roots; D010946:Plants, Medicinal; D053284:Polyunsaturated Alkamides / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D031364:Scutellaria baicalensis / Q000737:chemistry; D013431:Sulfates / Q000378:metabolism; D053719:Tandem Mass Spectrometry
chemical_list: D000470:Alkaloids; D052117:Benzodioxoles; D004365:Drugs, Chinese Herbal; D044950:Flavanones; D020719:Glucuronides; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D013431:Sulfates; D000082:Acetaminophen; C006680:baicalein; D002392:Catechin; D003474:Curcumin; C008922:piperine