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.