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Vol. 29, Issue 1, 48-53, January 2001

Use of Cloned and Expressed Human UDP-Glucuronosyltransferases for the Assessment of Human Drug Conjugation and Identification of Potential Drug Interactions

Brian T. Ethell, Kevin Beaumont, David J. Rance, and Brian Burchell

Department of Molecular and Cellular Pathology, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland (B.T.E., B.B.); and Department of Drug Metabolism (K.B.) and Project Management Department, Pfizer Central Research, Sandwich, Kent, United Kingdom (D.J.R.)

Glucuronidation is an important pathway for human drug metabolism. Four cloned and expressed human UDP-glucuronosyltransferases (UGT1A1, UGT1A6, UGT1A9, and UGT2B15) were used to screen a series of three potential drug substrates differing only in position of the phenol moiety. The meta and para phenols, UK-156,037 and UK-157,147, were found to be substrates for UGT1A1 with Km values of 256 and 105 µM, respectively. The ortho phenol UK-157,261 was glucuronidated predominantly by UGT1A9 with a Km of 45 µM. The latter Km compares favorably with the known UGT1A9 substrate propofol (Km = 200 µM). In a series of competition experiments, UK-157,261 was shown to inhibit the glucuronidation of propofol by UGT1A9 with a Ki value of 65 µM. This result indicates that even the most potent of these compounds is extremely unlikely to interact in the clinic with the glucuronidation of propofol. This study shows the utility of the expressed human UDP-glucuronosyltransferases in determining substrate structure-activity relationships and potential drug-drug interactions.

Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics


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Copyright © 2001 by the American Society for Pharmacology and Experimental Therapeutics.