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First Pass Metabolism and in Vitro Metabolism of a New Orally Active Dopamine Prodrug, N-(N-acetyl-L-methionyl)-O,O-bis(ethoxycarbonyl)dopamine in Dogs

First Pass Metabolism and in Vitro Metabolism of a New Orally Active Dopamine Prodrug, N-(N-acetyl-L-methionyl)-O,O-bis(ethoxycarbonyl)dopamine in Dogs

M Yoshikawa, S Nishiyama, H Endo, Y Togo, O Takaiti

Drug Metab Dispos. Sep-Oct 1991;19(5):960-5.

PMID: 1686243

Abstract:

To elucidate the first pass metabolism of the dopamine prodrug N-(N-acetyl-L-methionyl)-O,O-bis(ethoxycarbonyl)dopamine (TA-870) in the small intestine and liver of dogs, the blood and plasma concentrations of unchanged TA-870 and metabolites in the gastroduodenal vein, portal vein, hepatic vein, and abdominal aorta were measured by HPLC after intraduodenal administration of TA-870. In addition, an in vitro metabolic study of TA-870 was carried out using liver, small intestinal wall, and blood homogenates of dogs. The order of maximal concentration (Cmax 0-30 min) in gastroduodenal blood or plasma was unchanged TA-870 greater than deethoxycarbonylated TA-870 (DEC-TA-870) greater than conjugated dopamine greater than free dopamine (DA) greater than free homovanillic acid (HVA) greater than free 3,4-dihydroxyphenylacetic acid (DOPAC). This result showed that the main pathway of metabolism in the small intestine is catechol ester hydrolysis and minor pathways are amido hydrolysis, oxidative deamination, and catechol 3-O-methylation. The order of Cmax in the hepatic vein and abdominal aorta was conjugated DA greater than free DEC-TA-870 greater than free HVA greater than free DA greater than free DOPAC greater than conjugated DOPAC greater than unchanged TA-870. The main metabolic pathways in the liver were hydrolyses of ester and amido-linkage of TA-870 and conjugation of DA. In the in vitro studies, the main metabolites of TA-870 in liver, small intestinal wall, and blood homogenates were DEC-TA-870, 3- or 4-mono-deethoxycarbonylated TA-870, DA, and an unknown compound.(ABSTRACT TRUNCATED AT 250 WORDS)

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP142172518	4-Bromo-1-butylboronic acid catechol ester		142172-51-8	Price

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