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Drug Metabolism and Disposition Fast Forward
First published on June 24, 2005; DOI: 10.1124/dmd.105.005108

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Received for publication April 11, 2005.
Revised June 13, 2005.
Accepted for publication June 17, 2005.

UDP-GLUCURONOSYLTRANSFERASE 2B7 IS THE MAJOR ENZYME RESPONSIBLE FOR GEMCABENE GLUCURONIDATION IN HUMAN LIVER MICROSOMES

Jonathan N Bauman 1*, Theunis C Goosen 1, Meera Tugnait 2, Susan I Hurst 2, Vincent Peterkin 2, Mark Milad 2, Michael Court 3, Lee Menning 2, James A Williams 2

1 Pfizer Global R&D 2 Pfizer 3 Tufts

* Address correspondence to: E-mail: jonathan.bauman{at}pfizer.com

Abstract

The predominant metabolic pathway of gemcabene in humans is glucuronidation. The principal human UDP-glucuronosyltransferases (UGTs) involved in the glucuronidation of gemcabene were determined in this study. Glucuronidation of gemcabene was catalyzed by recombinant UGT1A3, recombinant UGT2B7 and recombinant UGT2B17, as well as by HLM. Gemcabene glucuronidation in recombinant UGTs and HLM followed non-Michaelis-Menten kinetics consistent with homotropic activation, but pharmacokinetics in humans were linear over the dose range tested (total plasma Cmax 0.06-0.88 mM). Gemcabene showed similar affinity (S50) for recombinant UGTs (0.92 -1.45 mM) and HLM (1.37 mM). (S)-Flurbiprofen was identified as a more selective inhibitor of recombinant UGT2B7-catalyzed gemcabene glucuronidation (>23-fold lower IC50) when compared with recombinant UGT1A3- or recombinant UGT2B17-catalyzed gemcabene glucuronidation. The IC50 for (S)-flurbiprofen inhibition of gemcabene glucuronidation was similar in HLM (60.6 µM) compared with recombinant UGT2B7 (27.4 µM), consistent with a major role for UGT2B7 in gemcabene glucuronidation in HLM. In addition, 5, 6, 7, 3', 4', 5'-hexamethoxyflavone (HMF) inhibited recombinant UGT1A3 and recombinant UGT2B17-catalyzed gemcabene glucuronidation (with 4-fold greater potency for recombinant UGT1A3), but did not inhibit gemcabene glucuronidation in HLM, suggesting that UGT1A3 and UGT2B17 do not contribute significantly to gemcabene glucuronidation. Reaction rates for gemcabene glucuronidation from a human liver bank (r2 = 0.722, P<0.0001, n=24) correlated well with rates of glucuronidation of the UGT2B7 probe substrate 3'-azido-3'-deoxythymidine (AZT). In conclusion, using the three independent experimental approaches typically utilized for cytochrome P450 reaction phenotyping, UGT2B7 is the major enzyme contributing to gemcabene glucuronidation in human liver microsomes.


Key words: allosterism, enzyme kinetics, glucuronidation, inhibition, microsomes, phase II drug metabolism, UDP glucuronyltransferases


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