N-glucuronidation reactions. II. Relative N-glucuronidation reactivity of 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 incubated with UDP-glucuronic acid-enriched liver microsomes from rats, monkeys, and humans. These compounds, all methylbiphenyl (MB) derivatives, represent three classes of N-containing heterocycles commonly used in the design of new drug entities [i.e MB-tetrazole, MB-triazole, (1,2,3- and 1,2,4-), and MB-imidazole (C2- and C4-substituted)]. The structures of all respective N-glucuronides generated from microsomal incubations 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 both nitrogens are in immediate neighboring positions of the substituted carbon, was unreactive toward N-glucuronidation. When the rate of N-glucuronidation was compared under optimal reaction conditions for each compound, most compounds showed higher reactivity with liver microsomes from monkeys than those from rats, except for N2-glucuronidation of MB-tetrazole and MB-1,2,3-triazole. However, the trend for the relative N-glucuronidation reactivity of these compounds by liver microsomes from humans is quite different from those by monkeys and rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Drug Metabolism, Merck Research Laboratories, Rahway, NJ 07065.
S W
SW
Huskey
G A
GA
Doss
R R
RR
Miller
W R
WR
Schoen
S H
SH
Chiu
D000818:Animals; D001665:Binding Sites; D001713:Biphenyl Compounds / Q000378:metabolism*; D004795:Enzyme Stability; D005965:Glucuronates / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007093:Imidazoles / Q000378:metabolism*; D008253:Macaca mulatta; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D009584:Nitrogen / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D013777:Tetrazoles / Q000378:metabolism*; D014230:Triazoles / Q000378:metabolism*
D001713:Biphenyl Compounds; D005965:Glucuronates; D007093:Imidazoles; D013777:Tetrazoles; D014230:Triazoles; D009584:Nitrogen