DMD Simcyp

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

0090-9556/03/3108-1027-1034$20.00
DMD 31:1027-1034, 2003

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Ethell, B. T.
Right arrow Articles by Burchell, B.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Ethell, B. T.
Right arrow Articles by Burchell, B.

GLUCURONIDATION OF HMR1098 IN HUMAN MICROSOMES: EVIDENCE FOR THE INVOLVEMENT OF UGT1A1 IN THE FORMATION OF S-GLUCURONIDES

Brian T. Ethell, Jens Riedel, Heinrich Englert, Herbert Jantz, Raymond Oekonomopulos, and Brian Burchell

Department of Molecular and Cellular Pathology, Ninewells Medical School, University of Dundee, Dundee, Scotland (B.T.E., B.B.); and Drug Metabolism/Pharmacokinetics, Aventis Pharma Deutschland GmbH, Frankfurt am Main, Germany (J.R., H.E., H.J., R.O.)

HMR1098, a novel KATP-blocking agent, is metabolized to form an S-glucuronide in rat and dog bile. Synthesis of the S-glucuronide metabolite was studied in human liver and kidney microsomes. Recombinant UPD-glucuronosyltransferases (UGTs) were screened for activity, and kinetic analysis was performed to identify the isoform or isoforms responsible for the formation of this novel S-glucuronide in humans. S-Glucuronidation is relatively rare, but from this study it appears that S-glucuronides are not generated exclusively by a single UGT isoform. From the panel of recombinant isoforms used, both UGT1A1 and UGT1A9 catalyzed the glucuronidation of HMR1098. The Vmax values in both instances were similar, but the Km for UGT1A1 was substantially lower than that measured for UGT1A9, 82 µM compared with 233 µM, respectively. Liver and kidney microsomes displayed similar Km values, but the Vmax in kidney was more than 20-fold less than in liver microsomes, which is suggestive of a significant role for the bilirubin UGT in catalysis of HMR1098, although other UGTs may play a secondary role.

Address correspondence to: Dr. Brian Burchell, Department of Molecular and Cellular Pathology, Ninewells Hospital and Medical School, The University of Dendee, Dundee, Scotland, DD1 9SY, UK. E-mail: b.burchell{at}dundee.ac.uk




This article has been cited by other articles:


Home page
 Drug Metab. Dispos.Home page
K. A. Keating, O. McConnell, Y. Zhang, L. Shen, W. Demaio, L. Mallis, S. Elmarakby, and A. Chandrasekaran
NMR CHARACTERIZATION OF AN S-LINKED GLUCURONIDE METABOLITE OF THE POTENT, NOVEL, NONSTEROIDAL PROGESTERONE AGONIST TANAPROGET
Drug Metab. Dispos., August 1, 2006; 34(8): 1283 - 1287.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
D. Zhang, W. Zhao, V. A. Roongta, J. G. Mitroka, L. J. Klunk, and M. Zhu
AMIDE N-GLUCURONIDATION OF MAXIPOST CATALYZED BY UDP-GLUCURONOSYLTRANSFERASE 2B7 IN HUMANS
Drug Metab. Dispos., May 1, 2004; 32(5): 545 - 551.
[Abstract] [Full Text] [PDF]


Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2003 by the American Society for Pharmacology and Experimental Therapeutics.