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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on August 3, 2004; DOI: 10.1124/jpet.104.073114

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Received for publication June 24, 2004.
Revised July 30, 2004.
Accepted for publication July 30, 2004.

N-Glucuronidation of Carbamazepine in Human Tissues is Mediated by UGT2B7

Adam G. Staines 1, Michael W.H. Coughtrie 1*, Brian Burchell 1

1 University of Dundee

* Address correspondence to: E-mail: m.w.h.coughtrie{at}dundee.ac.uk

Abstract

Carbamazepine (CBZ) is one of the most widely prescribed anticonvulsants despite a high incidence of idiosyncratic side effects. Metabolism of CBZ is complex, and of the more than 30 metabolites identified to date one of the most abundant is CBZ N-glucuronide. To date the UGT isoform responsible for the N-glucuronidation of CBZ has not been identified. We have developed a sensitive liquid chromatography/mass spectrometry assay to quantify CBZ glucuronidation, and we report that CBZ is specifically glucuronidated by human UGT2B7. Kinetics of CBZ glucuronidation in human liver, kidney and intestine microsomes were consistent with those of recombinant UGT2B7 which displayed a Km of 214 µM and Vmax of 0.79 pmol/mg/min. In addition to revealing the isoform responsible for CBZ glucuronidation, this is the first example of primary amine glucuronidation by UGT2B7.


Key words: UDP-glucuronosyltransferase, adverse drug reactions, anticonvulsant, carbamazepine, glucuronidation, human tissues


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