Characterization of benzazepine UDP-glucuronosyl-transferases in laboratory animals and man

1. The O-glucuronidation of two dopamine D1 receptor antagonists, Odapipam and Berupipam, were studied in hepatic microsomal fractions from mouse, rat, rabbit, dog, pig, and man using 14C-UDP-glucuronic acid. 2. The influence of pH, detergent, gender, drug-metabolizing enzyme inducers, and age were examined. Detergents like the zwitterionic CHAPS and non-ionic Tween 20, Triton X-100, and Brij 35 stimulated the glucuronidation rate by up to 600% of native activity with the latter being most effective. Both apparent Km and Vmax increased following detergent treatment in rat hepatic microsomes. Less marked activation of UDP glucuronosyltransferase activity was observed with Brij 35 in mouse, rabbit, dog, and pig compared with rat. In contrast, human hepatic microsomes were not stimulated by detergent treatment. 3. Marked species-dependent UDP-glucuronosyltransferase activity were observed for the two compounds. In general, Odapipam exhibited higher Vmax and Km compared with Berupipam with the exception of rabbit where the reverse was true. Similar kinetic parameters were, however, observed in human hepatic microsomes. Highest glucuronidation rate (in general) was observed in mouse followed by dog, pig, rabbit, man, and rat. 4. UGT activity in human livers showed up to a seven-fold variation. Conjugation of each compound were highly correlated (r = 0.92; n = 20) suggesting that identical isoform(s) were involved in this reaction. A significant age-related decrease in UDP-glucuronosyltranferase activity was observed, which partly could be explained by a preponderance in elderly female donor liver samples.