Abstract
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 withKm 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 aKi 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.
Footnotes
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Send reprint requests to: Brian T. Ethell, Department of Molecular and Cellular Pathology, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, Scotland. E-mail:b.ethell{at}dundee.ac.uk
- Abbreviations used are::
- UGT
- UDP-glucuronosyltransferase
- UDPGA
- UDP-glucuronic acid
- HPLC
- high-performance liquid chromatography
- HLM
- human liver microsome
- Received July 13, 2000.
- Accepted September 21, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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