RT Journal Article SR Electronic T1 In vitro metabolism of the new cardiotonic agent denopamine (TA-064) by rat and rabbit liver preparations. Oxidation, methylation, and glucuronidation. JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 246 OP 254 VO 13 IS 2 A1 T Suzuki A1 Y Hashimura A1 S Takeyama YR 1985 UL http://dmd.aspetjournals.org/content/13/2/246.abstract AB The metabolic pathways of the cardiotonic agent denopamine, (-)-(R)-1-(p-hydroxyphenyl)-2-[(3,4-dimethoxyphenethyl)amino]ethanol, were studied in vitro with rat and rabbit liver preparations. 4'-O-Demethylated (M-1), 3'-O-demethylated (iso-M-1), and 3-hydroxylated (M-4) metabolites of denopamine were formed by incubation of denopamine with the rat liver microsomal fraction containing the NADPH-generating system. The ratio of M-1 to iso-M-1 formed in this system was 33:1. 3-Methoxydenopamine (M-2) and 3-hydroxy-4-O-methyldenopamine (iso-M-2) were formed via the catechol intermediate M-4, when denopamine was incubated with the rat liver 9000g supernatant fraction in the presence of the NADPH-generating system and S-adenosyl-L-methionine. The ratio of M-2 to iso-M-2 in this system was 7:1. Conversion of iso-M-2 to M-2, i.e. 4-O-demethylation followed by 3-O-methylation, but not vice versa, took place in this system. M-2 was demethylated at 4' to form M-3 by the above microsomal system. M-1 was not ring-hydroxylated by this system, excluding the metabolic route to M-3 via M-1. Denopamine, M-1, M-2, and M-3 were glucuronidated in vitro by the rabbit liver microsomal fraction. The glucuronides of denopamine and M-2 were conjugated at the 4-phenolic hydroxy group, and the glucuronides of M-1 and M-3, which possess two phenolic hydroxy groups, were preferentially conjugated at the 4'-hydroxy group. The order of the rates of in vitro glucuronidation was M-3 greater than M-1 greater than M-2 greater than denopamine.