Yamaguchi I, Nishiyama S, Akimoto Y, Yoshikawa M, Nakajima H
Biological Research Laboratory, Tanabe Seiyaku Co., Ltd., Toda, Japan.
J Cardiovasc Pharmacol. 1989 Jun;13(6):879-86. doi: 10.1097/00005344-198906000-00010.
Intraduodenal administration of N-(N-acetyl-L-methionyl)-O, O-bis(ethoxycarbonyl)dopamine (TA-870), a newly synthesized dopamine derivative, increased the renal blood flow (RBF) and mesenteric blood flow in anesthetized dogs, while blood pressure and heart rate were less affected. It also increased the glomerular filtration rate, urine volume, and urinary sodium excretion in saline-loaded anesthetized dogs. In conscious dogs, TA-870 and dopamine hydrochloride (DA-HCl) increased RBF in parallel with increases in plasma free dopamine (free-DA) concentration. At an equimolar dose of 71 mumols/kg, p.o., the effect of TA-870 continued for greater than 4 h, while that of DA-HCl lasted for only 2 h: the peak free-DA concentration and maximum increase in RBF were 155 +/- 57 ng/ml and 56 +/- 15%, respectively, for TA-870, and those for DA-HCl were 32 +/- 13 ng/ml and 36 +/- 10%. Similarly, TA-870 showed greater increases in both RBF and plasma free-DA concentration than DA-HCl in anesthetized rats. In contrast to enteral administration, intravenously administered TA-870 exhibited weaker effects than intravenous DA-HCl in anesthetized dogs. In conclusion, TA-870 is an orally effective dopamine prodrug capable of producing higher and more sustained plasma concentrations of dopamine than DA-HCl when administered by the enteral route.
新合成的多巴胺衍生物N-(N-乙酰-L-甲硫氨酰)-O,O-双(乙氧羰基)多巴胺(TA-870)经十二指肠给药可增加麻醉犬的肾血流量(RBF)和肠系膜血流量，而对血压和心率影响较小。它还可增加盐水负荷麻醉犬的肾小球滤过率、尿量和尿钠排泄。在清醒犬中，TA-870和盐酸多巴胺(DA-HCl)可使RBF增加，且与血浆游离多巴胺(free-DA)浓度升高平行。口服71 μmol/kg等摩尔剂量时，TA-870的作用持续超过4小时，而DA-HCl仅持续2小时：TA-870的游离多巴胺峰值浓度和RBF最大增加值分别为155±57 ng/ml和56±15%，DA-HCl则分别为32±13 ng/ml和36±10%。同样，在麻醉大鼠中，TA-870使RBF和血浆游离多巴胺浓度的升高幅度均大于DA-HCl。与肠内给药不同，在麻醉犬中，静脉注射TA-870的作用比静脉注射DA-HCl弱。总之，TA-870是一种口服有效的多巴胺前体药物，经肠内给药时能够产生比DA-HCl更高且更持久的多巴胺血浆浓度。
