Yoshikawa M, Nishiyama S, Endo H, Togo Y, Takaiti O
Biological Research Laboratory, Tanabe Seiyaku Co., Ltd., Toda Saitama, Japan.
Drug Metab Dispos. 1991 Sep-Oct;19(5):960-5.
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)
为阐明多巴胺前体药物N-(N-乙酰基-L-甲硫氨酰基)-O,O-双(乙氧羰基)多巴胺(TA-870)在犬小肠和肝脏中的首过代谢，经十二指肠给予TA-870后，采用高效液相色谱法测定胃十二指肠静脉、门静脉、肝静脉和腹主动脉中未变化的TA-870及其代谢产物的血药浓度和血浆浓度。此外，还利用犬的肝脏、小肠壁和血液匀浆进行了TA-870的体外代谢研究。胃十二指肠血液或血浆中最大浓度(Cmax 0 - 30分钟)的顺序为：未变化的TA-870 > 脱乙氧羰基化TA-870(DEC-TA-870) > 结合多巴胺 > 游离多巴胺(DA) > 游离高香草酸(HVA) > 游离3,4-二羟基苯乙酸(DOPAC)。该结果表明，小肠中的主要代谢途径是儿茶酚酯水解，次要途径是酰胺水解、氧化脱氨基和儿茶酚3-O-甲基化。肝静脉和腹主动脉中Cmax的顺序为：结合DA > 游离DEC-TA-870 > 游离HVA > 游离DA > 游离DOPAC > 结合DOPAC > 未变化的TA-870。肝脏中的主要代谢途径是TA-870的酯键和酰胺键水解以及DA的结合。在体外研究中，TA-870在肝脏、小肠壁和血液匀浆中的主要代谢产物为DEC-TA-870、3-或4-单脱乙氧羰基化TA-870、DA和一种未知化合物。(摘要截取自250字)
