作者: Risto O. Juvonen , Aki T. Heikkinen , Olli Kärkkäinen , Rabia Jehangir , Juhani Huuskonen
DOI: 10.1016/J.EJPS.2019.105118
关键词:
摘要: Abstract Beagle dog is a standard animal model for evaluating nonclinical pharmacokinetics of new drug candidates. Glucuronidation in intestine and liver an important first-pass metabolic pathway, especially phenolic compounds. This study evaluated the glucuronidation characteristics several 7-hydroxycoumarin derivatives beagle dog's vitro. To this end, rates (compound 1), 7-hydroxy-4-trifluoromethylcoumarin (2), 6-methoxy-7-hydroxycoumarin (3), 7-hydroxy-3-(4-tolyl)coumarin (4), 3-(4-fluorophenyl)coumarin (5), 7-hydroxy-3-(4-hydroxyphenyl)coumarin (6), 7-hydroxy-3-(4-methoxyphenyl)coumarin (7), 7-hydroxy-3-(1H-1,2,4-tirazole)coumarin (8) were determined microsomes, as well recombinant UGT1A enzymes. The 1, 2 3 3–10 times higher than small whereas 5, 6, 7 8 similar microsomes from both tissues. In colon, 1 was 3–5 faster intestine. dUGT1A11 glucuronidated efficiently all substrates more efficient catalyst any other dUGT1A. Other active enzymes dUGT1A2 that 2, 3, 4, 6 7, while dUGT1A10 5 7. Kinetic analyses revealed compounds’ Km values varied between 1.1 (dUGT1A10 2) 250 µM (dUGT1A7 4). results further strengthen concept has high capacity glucuronidation, different dUGT1As mediate with distinct selectivity human.