N-glucuronidation reactions. I. Tetrazole N-glucuronidation of selected angiotensin II receptor antagonists in hepatic microsomes from rats, dogs, monkeys, and humans.
In vitro conditions for the preparation of tetrazole N2-glucuronides using liver microsomes (enriched with UDP-glucuronic acid) from rats, dogs, monkeys, and humans have been developed and optimized. The structures of tetrazole N2-glucuronides of 3 biphenyl tetrazole-containing angiotensin II (AII) receptor antagonists MK-954 (I), L-158,338 (II), and L-158,809 (III), and a model compound methyl biphenyl tetrazole (IV) were determined either by NMR and mass spectrometry or by comparison of HPLC retention times with that from authentic compounds. The species difference as well as gender difference in the rate of the in vitro reaction were compared. The optimal pH for the reaction was determined to be 5.0 with liver microsomes from monkeys and humans, and 6.2 with those from rats and dogs. For the model compound IV, the rate of N2-glucuronidation by liver microsomes from rats, dogs, and monkeys was approximately 10-fold faster than that by humans. For the AII receptor antagonists I, II, and III, the rate of the same reaction by liver microsomes from dogs and monkeys was much faster than that by humans. The relative intrinsic rate of this reaction for these three substrates ranked similarly in rats and humans as II > III > I. With compound I, a biphenyl tetrazole-containing imidazole derivative that has potential sites for both O- (primary hydroxyl) and N2-(tetrazole) glucuronidation, both O- and tetrazole N2-glucuronides were formed by liver microsomes from rats and monkeys (at neutral pH), whereas N2-glucuronide was the only product from dogs and humans.(ABSTRACT TRUNCATED AT 250 WORDS)
Huskey
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Department of Animal and Exploratory Drug Metabolism, Merck Research Laboratories, Rahway, NJ 07065.
Miller
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Chiu
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D000804:Angiotensin II / Q000037:antagonists & inhibitors / Q000378:metabolism*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001713:Biphenyl Compounds / Q000378:metabolism; D004285:Dogs; D004790:Enzyme Induction; D005260:Female; D005965:Glucuronates / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D007093:Imidazoles / Q000378:metabolism; D007700:Kinetics; D019808:Losartan; D008253:Macaca mulatta; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D013777:Tetrazoles / Q000378:metabolism*
D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D005965:Glucuronates; D007093:Imidazoles; D013777:Tetrazoles; D000804:Angiotensin II; D019808:Losartan