Metabolism of γ-glutamyl dopamide and its carboxylic acid esters

The release of dopamine (DA) from L-γ-glutamyl dopamide (GDA) during incubation with renal homogenates from the dog was catalyzed by γ-glutamyltranspeptidase. This was shown by the increased release in the presence of glycylglycine, by the formation and isolation of glutamylglycylglycine, and by the complete inhibition of release by a combination of serine and tetraborate. Cleavage was localized predominantly in the renal cortex. Carboxylic acid esters of GDA were extremely effective prodrugs for DA, as measured by the increased renal DA level following their intragastric or intraperitoneal administration to rats. There was a close correlation between the in vitro susceptibility of the esters to hydrolysis by hepatic esterase and the renal level of DA following their intragastric administration; the n -amyl, n -hexyl and benzyl esters were very active in both tests. Hydrolysis of the ester bond appeared to be the most decisive step among those that occur during the transport of DA in the form of a GDA ester in the intestine to unbound DA in the kidney. When esters were administered intraperitoneally, renal DA levels were approximately 100 times higher than after intragastric administration, and the largest increases were produced by the n -heptyl and n -octyl esters; little correlation existed between the rate of ester hydrolysis and renal DA level. Because of the intensive renal activity of γ-glutamyltranspeptidase, it is likely that most of the DA appearing in kidney from GDA and its carboxylic acid esters is released within the kidney itself and does not originate in other body organs.