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

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概要

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• 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 > homovanillic acid (HVA) > 3,4-dihydroxyphenylacetic acid (DOPAC) > 3-hydroxyphenylacetic acid (3-HPAC). Those in dogs (33.5 mg/kg p.o.) were DA > HVA > de-ethoxycarbonylated TA-870 (DEC-TA-870) ≒ 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 > DOPAC > HVA > 3-HPAC, while those in dogs (13.5 mg/kg) were DOPAC > DA > 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. After i.v. administration of TA-870 (30 mg/kg) to rats, the order of urinary excretion was HVA > DA > DOPAC > 3-HPAC ; the excretion of HVA being higher than that after p.o. dosing. Most of DA and DEC-TA-870 were excreted as the conjugated form in the urine. In rats, the biliary excretion of radioactivity after p. o. dosing of ^<14>C-TA-870 was 30.7% of the dose, being lower than that in urine.

著者

• SUGAWARA Yoichi

  Biological Research Laboratory, Tanabe Seiyaku Co. Ltd.

• TAKAITI Osasi

  Biological Research Laboratory, Tanabe Seiyaku Co. Ltd.

• Yoshikawa Masayoshi

  Biological Research Laboratory Tanabe Seiyaku Co. Ltd.

• Takaiti O

  Tanabe Seiyaku Co. Ltd. Saitama Jpn

• Komatsu Kumiko

  Biological Research Laboratory Tanabe Seiyaku Co. Ltd.

• ENDO Hiroshi

  Biological Research Laboratory, Tanabe Seiyaku Co., Ltd.

• Sugawara Yoichi

  Biological Research Laboratory Tanabe Seiyaku Co. Ltd.

• Endo H

  Toshiba Corp. Yokohama

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