@article {Perrier91, author = {L Perrier and M Bourri{\'e} and E Marti and C Tronquet and D Mass{\'e} and Y Berger and J Magdalou and G Fabre}, title = {In vitro N-glucuronidation of SB 47436 (BMS 186295), a new AT1 nonpeptide angiotensin II receptor antagonist, by rat, monkey and human hepatic microsomal fractions.}, volume = {271}, number = {1}, pages = {91--99}, year = {1994}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {The glucuronidation of the AT1 nonpeptide angiotensin II receptor antagonist, SR 47436 (BMS 186295), was investigated in hepatic microsomes prepared from various species, i.e., Sprague-Dawley rat, Cynomolgus monkey and Caucasian humans. The drug was found to undergo N-glucuronidation on the tetrazole moiety as confirmed by its hydrolysis by beta-glucuronidase, its associated radioactivity when UDP-[U-14C]glucuronic acid was used as substrate and by different techniques such as high-performance liquid chromatography-mass spectrometry and nuclear magnetic resonance. Glucuronide formation was optimal at pH 5.0 along with a "0.2 mg of Brij 58 per mg of protein" ratio, regardless of the investigated species. Cynomolgus monkey microsomes glucuronidated SR 47436 (BMS 186295) to the greatest extent, with a relative catalytic efficiency 11.0- and 2.6-fold higher than that observed in rat and human, respectively. SR 47436 (BMS 186295) glucuronidation followed Michaelis-Menten kinetics. Bilirubin:UDP-glucuronosyltransferase isoform was not involved, inasmuch as bilirubin did not affect its glucuronidation, 7,7,7-triphenylheptanoic acid was a noncompetitive inhibitor and glucuronidation was only decreased 2-fold in Gunn rats. SR 47436 (BMS 186295) glucuronidation was enhanced markedly after treatment of rats with dexamethasone (Vmax/Km = 71.5 vs. 2.6 in untreated animals). Among the drugs used which undergo phenolic, carboxylic acid, alcohol or tertiary amine glucuronidation, only monodigitoxigenin-monodigitoxoside, flurbiprofen, naproxen, testosterone and estrone inhibited SR 47436 (BMS 186295) glucoronidation in a noncompetitive manner. These data suggest that SR 47436 (BMS 186295) was glucuronidated by a highly dexamethasone-inducible UDP-glucuronosyltransferase isoform(s), different from that involved in the glucuronidation of monodigitoxigenin-monodigitoxoside.}, issn = {0022-3565}, URL = {https://jpet.aspetjournals.org/content/271/1/91}, eprint = {https://jpet.aspetjournals.org/content/271/1/91.full.pdf}, journal = {Journal of Pharmacology and Experimental Therapeutics} }