Metabolism of denopamine, a new cardiotonic agent, in the rat and dog.
The metabolism of denopamine, (R)-(-)-1-(p-hydroxyphenyl)-2-[(3,4-dimethoxyphenethyl)amino] ethanol, a new, orally active, selectively inotropic cardiotonic agent, was studied in the rat and dog. Animals were given single oral doses of 5 mg/kg of denopamine labeled with 14C. Denopamine was metabolized in the rat and dog by several pathways including conjugation, side chain oxidation, and ring hydroxylation followed by O-methylation. Rats excreted the drug in the urine almost entirely as unchanged drug and its phenolic O-glucuronide whereas in the dog, the major metabolites were the phenolic O-glucuronide, the alcoholic O-glucuronide, and the phenolic O-sulfate of denopamine and the phenolic O-glucuronide of 3-methoxydenopamine. Demethylation, which has been shown to be a major metabolic pathway in man, and side chain oxidation were minor pathways in the rat and dog. Furthermore, a high degree of stereoselective resistance of the alcoholic O-glucuronide of denopamine to hydrolysis by beta-glucuronidase was observed.
Furuuchi
S
S
Naito
K
K
Otsuka
M
M
Harigaya
S
S
D000818:Animals; D002316:Cardiotonic Agents / Q000378:metabolism*; D004285:Dogs; D004983:Ethanolamines / Q000378:metabolism*; D005965:Glucuronates / Q000378:metabolism; D005966:Glucuronidase / Q000494:pharmacology; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013045:Species Specificity; D013237:Stereoisomerism
D002316:Cardiotonic Agents; D004983:Ethanolamines; D005965:Glucuronates; D005966:Glucuronidase; C037293:denopamine