Renal selective N-acetyl-gamma-glutamyl prodrugs: a study on the mechanism of activation of the renal vasodilator prodrug CGP 22979.
1. In this study the processes underlying the renal selectivity of the vasodilator prodrug CGP 22979 (N-acetyl-L-glutamic acid-N-[N2-(5-n-butyl-2-pyridyl) hydrazide]) were studied in rats. 2. The active drug CGP 18137 (2-hydrazino-5-n-butyl pyridine) selectively accumulated in the renal tissue following administration of the prodrug. 3. The kidney concentrations of active drug following prodrug administration were significantly lower than control values when either buthionine sulphoximine, glutathione or probenecid was coadministered (29 +/- 11; 33 +/- 14 and 61 +/- 20% of control values, respectively). Inhibition of gamma-glutamyl transpeptidase by AT-125 did not cause a significant decrease of renal CGP 18137 levels. 4. In order to correlate tissue drug concentrations with pharmacological effect, the renal haemodynamic responses to CGP 22979 were measured and the effect of buthionine sulphoximine, glutathione and AT-125 on these responses evaluated. All three of the compounds attenuated the renal response to the prodrug: an approximately 50% lesser decrease in renal resistance was found. The compounds had no effect on the haemodynamic actions of CGP 18137 itself. 5. In vitro, it was found that kidney cytosol was able to convert the prodrug, whereas microsomes were not, unless acylase was added. 6. The results indicate that, upon prodrug administration, gamma-glutamyl transpeptidase is not involved in the renal accumulation of CGP 18137 but is partly responsible for the renal haemodynamic responses to CGP 22979. Active transport of the prodrug into the tubular cells appears to be the major reason for the renal selectivity. A model is proposed for the renal action of CGP 22979, in which the important parts are the uptake of the prodrug via a transport system followed by an intracellular conversion to the active drug.
Drieman
J C
JC
Department of Pharmacology, University of Limburg, Maastricht, The Netherlands.
Thijssen
H H
HH
Zeegers
H H
HH
Smits
J F
JF
Struyker Boudier
H A
HA
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D006439:Hemodynamics / Q000187:drug effects; D006834:Hydrazines / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology*; D066298:In Vitro Techniques; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D011355:Prodrugs; D051381:Rats; D011918:Rats, Inbred SHR; D012079:Renal Circulation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*
D006834:Hydrazines; D011355:Prodrugs; D014665:Vasodilator Agents; C044760:N-acetylglutamic acid-N-(N(2)-(5-n-butyl-2-pyridyl)hydrazide); C044759:2-hydrazino-5-n-butylpyridine