A novel orally active dopamine prodrug TA-870. I. Renal and cardiovascular effects and plasma levels of free dopamine in dogs and rats.
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.
Yamaguchi
I
I
Biological Research Laboratory, Tanabe Seiyaku Co., Ltd., Toda, Japan.
Nishiyama
S
S
Akimoto
Y
Y
Yoshikawa
M
M
Nakajima
H
H
D000284:Administration, Oral; D000704:Analysis of Variance; D000818:Animals; D004231:Diuresis / Q000187:drug effects*; D004285:Dogs; D004298:Dopamine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood* / Q000493:pharmacokinetics / Q000494:pharmacology; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D008297:Male; D011355:Prodrugs / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D012079:Renal Circulation / Q000187:drug effects*; D013152:Splanchnic Circulation / Q000187:drug effects
D011355:Prodrugs; C052143:docarpamine; D004298:Dopamine