PMID- 29240983
OWN - NLM
STAT- MEDLINE
DCOM- 20180813
LR  - 20181202
IS  - 1099-081X (Electronic)
IS  - 0142-2782 (Linking)
VI  - 39
IP  - 2
DP  - 2018 Feb
TI  - Human UGT2B7 is the major isoform responsible for the glucuronidation of 
      clopidogrel carboxylate.
PG  - 88-98
LID - 10.1002/bdd.2117 [doi]
AB  - Clopidogrel is predominantly hydrolyzed to clopidogrel carboxylic acid (CCA) by 
      carboxylesterase 1, and subsequently CCA is glucuronidated to clopidogrel acyl 
      glucuronide (CAG) by uridine diphosphate-glucuronosyltransferases (UGTs); 
      however, the UGT isoenzymes glucuronidating CCA remain unidentified to date. In 
      this study, the glucuronidation of CCA was screened with pooled human liver 
      microsomes (HLMs) and 7 human recombinant UGT (rUGT) isoforms. Results indicated 
      that rUGT2B7 exhibited the highest catalytical activity for the CCA 
      glucuronidation as measured with a mean V(max) value of 120.9 pmol/min/mg 
      protein, 3- to 12-fold higher than that of the other rUGT isoforms tested. 
      According to relative activity factor approach, the relative contribution of 
      rUGT2B7 to CCA glucuronidation was estimated to be 58.6%, with the minor 
      contributions (3%) from rUGT1A9. Moreover, the glucuronidation of CCA followed 
      Michaelis-Menten kinetics with a mean K(m) value of 372.9 muM and 296.4 muM for 
      pooled HLMs and rUGT2B7, respectively, showing similar affinity for both. The 
      formation of CAG was significantly inhibited by azidothymidine and gemfibrozil 
      (well-characterized UGT2B7 substrates) in a concentration-dependent manner, or by 
      fluconazole (a typical UGT2B7-selective inhibitor) in a time-dependent manner, 
      for both HLMs and rUGT2B7, respectively. In addition, CCA inhibited 
      azidothymidine glucuronidation (catalyzed almost exclusively by UGT2B7) by HLMs 
      and rUGT2B7 in a concentration-dependent manner, indicating that CCA is a 
      substrate of UGT2B7. These results reveal that UGT2B7 is the major enzyme 
      catalyzing clopidogrel glucuronidation in the human liver, and that there is the 
      potential for drug-drug interactions between clopidogrel and the other substrate 
      drugs of UGT2B7.
CI  - Copyright (c) 2017 John Wiley & Sons, Ltd.
FAU - Ji, Jin-Zi
AU  - Ji JZ
AD  - General Clinical Research Center, Nanjing First Hospital, Nanjing Medical 
      University, Nanjing, 210006, China.
FAU - Huang, Bei-Bei
AU  - Huang BB
AD  - General Clinical Research Center, Nanjing First Hospital, Nanjing Medical 
      University, Nanjing, 210006, China.
FAU - Gu, Tong-Tong
AU  - Gu TT
AD  - General Clinical Research Center, Nanjing First Hospital, Nanjing Medical 
      University, Nanjing, 210006, China.
FAU - Tai, Ting
AU  - Tai T
AD  - General Clinical Research Center, Nanjing First Hospital, Nanjing Medical 
      University, Nanjing, 210006, China.
FAU - Zhou, Huan
AU  - Zhou H
AD  - General Clinical Research Center, Nanjing First Hospital, Nanjing Medical 
      University, Nanjing, 210006, China.
AD  - Department of Clinical Pharmacy, School of Basic Medicine and Clinical Pharmacy, 
      China Pharmaceutical University, Nanjing, 211198, China.
FAU - Jia, Yu-Meng
AU  - Jia YM
AD  - General Clinical Research Center, Nanjing First Hospital, Nanjing Medical 
      University, Nanjing, 210006, China.
AD  - Department of Clinical Pharmacy, School of Basic Medicine and Clinical Pharmacy, 
      China Pharmaceutical University, Nanjing, 211198, China.
FAU - Mi, Qiong-Yu
AU  - Mi QY
AD  - General Clinical Research Center, Nanjing First Hospital, Nanjing Medical 
      University, Nanjing, 210006, China.
FAU - Zhang, Meng-Ran
AU  - Zhang MR
AD  - General Clinical Research Center, Nanjing First Hospital, Nanjing Medical 
      University, Nanjing, 210006, China.
FAU - Xie, Hong-Guang
AU  - Xie HG
AUID- ORCID: 0000-0002-1089-9457
AD  - General Clinical Research Center, Nanjing First Hospital, Nanjing Medical 
      University, Nanjing, 210006, China.
AD  - Department of Clinical Pharmacy, School of Basic Medicine and Clinical Pharmacy, 
      China Pharmaceutical University, Nanjing, 211198, China.
AD  - Departments of Pharmacology and Clinical Pharmacy, Nanjing Medical University 
      School of Pharmacy, Nanjing, 211166, China.
LA  - eng
PT  - Journal Article
DEP - 20180109
PL  - England
TA  - Biopharm Drug Dispos
JT  - Biopharmaceutics & drug disposition
JID - 7911226
RN  - 0 (Glucuronides)
RN  - 0 (Isoenzymes)
RN  - 0 (Recombinant Proteins)
RN  - 4B9XT59T7S (Zidovudine)
RN  - 8VZV102JFY (Fluconazole)
RN  - A74586SNO7 (Clopidogrel)
RN  - EC 2.4.1.- (UGT2B7 protein, human)
RN  - EC 2.4.1.17 (Glucuronosyltransferase)
RN  - OM90ZUW7M1 (Ticlopidine)
RN  - Q8X02027X3 (Gemfibrozil)
SB  - IM
MH  - Clopidogrel
MH  - Drug Interactions
MH  - Fluconazole/pharmacology
MH  - Gemfibrozil/pharmacology
MH  - Glucuronides/*metabolism
MH  - Glucuronosyltransferase/antagonists & inhibitors/*metabolism
MH  - Humans
MH  - Isoenzymes/metabolism
MH  - Kinetics
MH  - Microsomes, Liver/metabolism
MH  - Recombinant Proteins/metabolism
MH  - Ticlopidine/*analogs & derivatives/metabolism
MH  - Zidovudine/pharmacology
OTO - NOTNLM
OT  - UGT
OT  - clopidogrel
OT  - clopidogrel acyl glucuronide
OT  - clopidogrel carboxylate
OT  - glucuronidation
EDAT- 2017/12/15 06:00
MHDA- 2018/08/14 06:00
CRDT- 2017/12/15 06:00
PHST- 2017/09/05 00:00 [received]
PHST- 2017/11/20 00:00 [revised]
PHST- 2017/11/26 00:00 [accepted]
PHST- 2017/12/15 06:00 [pubmed]
PHST- 2018/08/14 06:00 [medline]
PHST- 2017/12/15 06:00 [entrez]
AID - 10.1002/bdd.2117 [doi]
PST - ppublish
SO  - Biopharm Drug Dispos. 2018 Feb;39(2):88-98. doi: 10.1002/bdd.2117. Epub 2018 Jan 
      9.