Synthesis and identification of the quaternary ammonium-linked glucuronide of 1-phenylimidazole in human liver microsomes and investigation of the human UDP-glucuronosyltransferases involved.
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.
Vashishtha
S C
SC
Drug Metabolism and Drug Disposition Group College of Pharmacy and Nutrition University of Saskatchewan Saskatoon, Saskatchewan, Canada.
Hawes
E M
EM
McKay
G
G
McCann
D J
DJ
D002851:Chromatography, High Pressure Liquid; D020719:Glucuronides / Q000737:chemistry / Q000378:metabolism*; D014453:Glucuronosyltransferase / Q000378:metabolism*; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008862:Microsomes, Liver / Q000378:metabolism*; D000644:Quaternary Ammonium Compounds / Q000737:chemistry*
D020719:Glucuronides; D007093:Imidazoles; D000644:Quaternary Ammonium Compounds; C037738:1-phenylimidazole; D014453:Glucuronosyltransferase