Yoshikawa M, Endo H, Komatsu K, Sugawara Y, Takaiti O
Biological Research Laboratory, Tanabe Seiyaku Co., Ltd., Saitama, Japan.
J Pharmacobiodyn. 1990 Apr;13(4):246-53. doi: 10.1248/bpb1978.13.246.
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)
通过薄层色谱法（TLC）和高效液相色谱法（HPLC）研究了口服活性多巴胺前药N-(N-乙酰-L-甲硫氨酰)-O,O-双(乙氧羰基)多巴胺（TA-870）和多巴胺（DA）的代谢情况，以鉴定和分析大鼠和犬经口和/或静脉给药后尿液和胆汁中的代谢产物。还测定了代谢产物的结合型/游离型比率。大鼠经口给予TA-870（30mg/kg）后，尿液中的代谢产物及其排泄顺序为：多巴胺＞高香草酸（HVA）＞3,4-二羟基苯乙酸（DOPAC）＞3-羟基苯乙酸（3-HPAC）。犬经口给予（33.5mg/kg）后为：多巴胺＞高香草酸＞脱乙氧羰基化TA-870（DEC-TA-870）≠3,4-二羟基苯乙酸。大鼠经口给予多巴胺（12mg/kg，与TA-870等摩尔剂量）后，尿液中的代谢产物及其排泄顺序为：多巴胺＞3,4-二羟基苯乙酸＞高香草酸＞3-羟基苯乙酸，而犬经口给予（13.5mg/kg）后为：3,4-二羟基苯乙酸＞多巴胺＞高香草酸。TA-870主要尿液代谢产物的组成在大鼠和犬中相似，但经口给予多巴胺后，犬中3,4-二羟基苯乙酸的排泄量比大鼠高得多（约3倍）。给予多巴胺和TA-870后，发现3-羟基苯乙酸是多巴胺的一种新代谢产物，推测它是由3,4-二羟基苯乙酸或多巴胺经肠道菌群脱羟基形成的。（摘要截短于250字）
