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)
Huskey
S W
SW
Department of Drug Metabolism, Merck Research Laboratories, Rahway, NJ 07065.
Doss
G A
GA
Miller
R R
RR
Schoen
W R
WR
Chiu
S H
SH
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