N-acyl-γ-glutamyl derivatives of sulfamethoxazole as models of kidney-selective prodrugs

M. Orlowski, H. Mizoguchi, S. Wilk

Research output: Contribution to journalArticlepeer-review

45 Scopus citations

Abstract

γ-Glutamyl and N-acyl-γ-glutamyl derivatives of sulfamethoxazole were synthesized and tested in mice as models of kidney selective prodrugs. In vitro, both D- and L-γ-glutamyl sulfamethoxazole are cleaved in the kidney by γ-glutamyl transpeptidase at a greatly higher rate than in other tissues. In vivo, compared with sulfamethoxazole, i.p. administration of the γ-glutamyl derivatives led to some preferential accumulation of the sulfonamide in the kidney. Relatively high concentrations of sulfamethoxazole were, however, found in other tissues, apparently because of rapid cleavage of the γ-glutamyl derivatives even in tissues with a low γ-glutamyl transpeptidase activity. Release of sulfamethoxazole in kidney homogenates from N-acyl-γ-glutamyl derivatives proceeds at a much slower rate than release of sulfamethoxazole from γ-glutamyl derivatives. This process requires the action of two enzymes, an N-acylamino acid deacylase and γ-glutamyl transpeptidase, both highly concentrated in the kidney. In vivo, a kidney selective accumulation of sulfamethoxazole was obtained 20 min after i.p. administration of N-acyl-γ-glutamyl derivatives. The concentration of sulfamethoxazole was 2.2 times higher after N-chloroacetyl-γ-glutamyl sulfamethoxazole than after an equimolar dose of sulfamethoxazole; the concentration in other tissues was only 2% of that in the kidney with somewhat higher concentrations in the liver. High kidney selectivity was also observed after the N-acetyl and N-butyryl-L-γ-glutamyl derivatives of sulfamethoxazole, although absolute kidney concentrations were lower. It is suggested that some N-acyl-γ-glutamyl derivatives of drugs might potentially be useful as kidney selective prodrugs, especially when systemic toxicity is a factor.

Original languageEnglish
Pages (from-to)167-172
Number of pages6
JournalJournal of Pharmacology and Experimental Therapeutics
Volume212
Issue number1
StatePublished - 1980
Externally publishedYes

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