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...

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Published inDrug metabolism and disposition Vol. 28; no. 9; pp. 1009 - 1013
Main Authors VASHISHTHA, S. C, HAWES, E. M, MCKAY, G, MCCANN, D. J
Format Journal Article
LanguageEnglish
Published Bethesda, MD American Society for Pharmacology and Experimental Therapeutics 01.09.2000
Subjects
Biological and medical sciences
Chromatography, High Pressure Liquid
General pharmacology
Glucuronides - chemistry
Glucuronides - metabolism
Glucuronosyltransferase - metabolism
Humans
Imidazoles - chemistry
Imidazoles - metabolism
Imidazoles - pharmacokinetics
Kinetics
Magnetic Resonance Spectroscopy
Medical sciences
Microsomes, Liver - metabolism
Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions
Pharmacology. Drug treatments
Quaternary Ammonium Compounds - chemistry
Human
Imidazole derivatives
UDP-glucuronosyltransferase
Enzyme
Transferases
Liver
Glycosyltransferases
Glucuronic acid conjugation
Metabolism
In vitro
Glucuroconjugate
Quaternary ammonium compound
Tertiary amine
Hexosyltransferases
Aromatic compound
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Summary: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.
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ISSN:0090-9556
1521-009X