Metabolism of a new orally active dopamine prodrug, N-(N-acetyl-L-methionyl)-O,O-bis(ethoxycarbonyl)dopamine (TA-870) and dopamine after oral administration to rats and dogs.

Abstract

The metabolism of an orally active dopamine prodrug, N-(N-acetyl-L-methionyl)-O,O-bis(ethoxycarbonyl)dopamine (TA-870) and of dopamine (DA), were studied by use of thin layer chromatography (TLC) and high performance liquid chromatography (HPLC) for identification and analysis of urinary and biliary metabolites after p.o. and/or i.v. administration to rats and dogs. The conjugated/free ratios of the metabolites were also determined. The urinary metabolites and order of the excretion in rats after p.o. dosing of TA-870 (30 mg/kg) were DA greater than homovanillic acid (HVA) greater than 3,4-dihydroxyphenylacetic acid (DOPAC) greater than 3-hydroxyphenylacetic acid (3-HPAC). Those in dogs (33.5 mg/kg p.o.) were DA greater than HVA greater than de-ethoxycarbonylated TA-870 (DEC-TA-870) not equal to DOPAC. The urinary metabolites and order of the excretion in rats after p.o. dosing of DA (12 mg/kg, equimolar dose to TA-870) were DA greater than DOPAC greater than HVA greater than 3-HPAC, while those in dogs (13.5 mg/kg) were DOPAC greater than DA greater than HVA. The composition of the main urinary metabolites of TA-870 are similar in rats and dogs but after p.o. dosing of DA, excretion of DOPAC in dogs is much (ca. 3 times) higher than that in rats. After administration of DA and TA-870, 3-HPAC was found as a novel metabolite of DA, which was thought to be formed by dehydroxylation of DOPAC or DA with intestinal flora.(ABSTRACT TRUNCATED AT 250 WORDS)