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Title: Herb–drug interaction prediction based on the high specific inhibition of andrographolide derivatives towards UDP-glucuronosyltransferase (UGT) 2B7

Herb–drug interaction strongly limits the clinical application of herbs and drugs, and the inhibition of herbal components towards important drug-metabolizing enzymes (DMEs) has been regarded as one of the most important reasons. The present study aims to investigate the inhibition potential of andrographolide derivatives towards one of the most important phase II DMEs UDP-glucuronosyltransferases (UGTs). Recombinant UGT isoforms (except UGT1A4)-catalyzed 4-methylumbelliferone (4-MU) glucuronidation reaction and UGT1A4-catalyzed trifluoperazine (TFP) glucuronidation were employed to firstly screen the andrographolide derivatives' inhibition potential. High specific inhibition of andrographolide derivatives towards UGT2B7 was observed. The inhibition type and parameters (K{sub i}) were determined for the compounds exhibiting strong inhibition capability towards UGT2B7, and human liver microsome (HLMs)-catalyzed zidovudine (AZT) glucuronidation probe reaction was used to furtherly confirm the inhibition behavior. In combination of inhibition parameters (K{sub i}) and in vivo concentration of andrographolide and dehydroandrographolide, the potential in vivo inhibition magnitude was predicted. Additionally, both the in vitro inhibition data and computational modeling results provide important information for the modification of andrographolide derivatives as selective inhibitors of UGT2B7. Taken together, data obtained from the present study indicated the potential herb–drug interaction between Andrographis paniculata and the drugs mainly undergoing UGT2B7-catalyzed metabolic elimination, and the andrographolidemore » derivatives as potential candidates for the selective inhibitors of UGT2B7. - Highlights: • Specific inhibition of andrographolide derivatives towards UGT2B7. • Herb-drug interaction related withAndrographis paniculata. • Guidance for design of UGT2B7 specific inhibitors.« less
Authors:
 [1] ;  [2] ;  [3] ;  [4] ;  [5] ;  [6] ;  [5] ;  [7] ;  [8] ;  [9] ; ;  [5] ; ;  [8] ;
  1. The Fourth Affiliated Hospital of China Medical University, Shenyang 110032 (China)
  2. School of Traditional Chinese Medicine, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang 110016 (China)
  3. The First Affiliated Hospital of Liaoning Medical University, Jinzhou 121001 (China)
  4. (China)
  5. Joint Center for Translational Medicine, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Zhongshan Road, Dalian 116023 (China)
  6. Thyroid Surgery, Yantaishan Hospital, Yantai, Shandong (China)
  7. (United States)
  8. Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892 (United States)
  9. Academy of Integrative Medicine, Dalian Medical University, Dalian 116044 (China)
Publication Date:
OSTI Identifier:
22439718
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 277; Journal Issue: 1; Other Information: Copyright (c) 2014 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; CONCENTRATION RATIO; DRUGS; ENZYMES; FORECASTING; HERBS; IN VITRO; IN VIVO; INHIBITION; LIVER; MICROSOMES