N-GLUCURONIDATION REACTIONS .2. RELATIVE N-GLUCURONIDATION REACTIVITYOF METHYLBIPHENYL TETRAZOLE, METHYLBIPHENYL TRIAZOLE, AND METHYLBIPHENYL IMIDAZOLE IN RAT, MONKEY, AND HUMAN HEPATIC MICROSOMES

The relative intrinsic in vitro N-glucuronidation reactivity of three classes of heterocyclic compounds was compared using model compounds i ncubated with UDP-glucuronic acid-enriched liver microsomes from rats, monkeys, and humans. These compounds, all methylbiphenyl (MB) derivat ives, represent three classes of N-containing heterocycles commonly us ed in the design of new drug entities [i.e MB-tetrarole, MB-triazole, (1,2,3- and 1,2,4-), and MB-imidazole (C2- and C4-substituted)]. The s tructures of all respective N-glucuronides generated from microsomal i ncubations were determined by Nuclear Overhauser Effect difference NMR spectroscopy. The chemical and enzymic stabilities of N-glucuronides were also studied. In general, relatively low reactivity was found at nitrogens located next to substituted carbons in heterocycles such as N3 in MB-C4-imidazole, N3 in MB-1,2,3-triazole, N2 (or N4) in MB-1,2,4 -triazole, and N1 (or N4) in MB-tetrazole. MB-C2-imidazole, in which b oth nitrogens are in immediate neighboring positions of the substitute d carbon, was unreactive toward N-glucuronidation. When the rate of N- glucuronidatian was compared under optimal reaction conditions for eac h compound, most compounds showed higher reactivity with liver microso mes from monkeys than those from rats, except for NS-glucuronidation o f MB-tetrazole and MB-1,2,3-triazole.