Abstract
1-Phenylimidazole was investigated as a potential model substrate with respect to formation of a quaternary ammonium-linked glucuronide (N+-glucuronide) at an aromatic type tertiary amine. A reference sample of the potential N+-glucuronide metabolite of 1-phenylimidazole was obtained by organic synthesis. The structural identity of the metabolite formed by incubation of 1-phenylimidazole with human liver microsomes was proven to be the N+-glucuronide by exhibiting the same HPLC retention time and electrospray ionization mass spectrum as the reference sample. The screening of 1-phenylimidazole against a panel of nine expressed human UDP-glucuronosyltransferases indicated the involvement of UGT1A3 and UGT1A4 in the formation of the N+-glucuronide metabolite.
Footnotes
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Send reprint requests to: Dr. Edward M. Hawes, Drug Metabolism and Drug Disposition Group, College of Pharmacy and Nutrition, 110 Science Place, University of Saskatchewan, Saskatoon, SK S7N 5C9, Canada.
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↵2 Present address: Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285.
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This study was supported by an AstraZeneca academic grant (to E.M.H. and D.J.M.). A part of this work was presented in abstract form at the 9th North American ISSX Meeting, October 24–29, 1999, Nashville, TN.
- Abbreviations used are::
- UGT
- UDP-glucuronosyltransferase
- UDPGA
- UDP-glucuronic acid
- ESI
- electrospray ionization
- MS
- mass spectrometry
- CHAPS
- (3-[3-cholamidopropyl)dimethylamino]-1-propane sulfonate
- Received March 24, 2000.
- Accepted May 19, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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