N-Acetyl-L-γ-glutamyl Derivatives of p-Nitroaniline,Sulphamethoxazole and Sulphamethizole for Kidney-specific Drug Delivery in Rats

Kidney-specific delivery of p-nitroaniline, sulphamethoxazole and sulphamethizole after either intravenous administration of the L-γ-glutamyl or N-acetyl-L-γ-glutamyl derivatives or the parent drugs has been examined in a rat model. All L-γ-glutamyl derivatives were converted to the corresponding parent drugs within 60 min whereas the N-acetyl-L-γ-glutamyl derivatives were fairly stable in the systemic circulation after parenteral administration. Concentrations of p-nitroaniline and sulphamethoxazole 20 min after administration of the parent drugs were somewhat higher in the kidney than in the liver and lung. The concentration of sulphamethizole in the kidney was dramatically higher than those in the hepatic and pulmonary tissue. Kidney-specific delivery of the drugs of interest was evaluated by determining the tissue concentrations of the released parent drug and the total drug levels (i.e. drug levels after hydrolysis of all conjugate to the parent drug). For L-γ-glutamyl-p-nitroaniline released renal levels of p-nitroaniline and total p-nitroaniline concentrations were both higher than those obtained after p-nitroaniline dosing. Use of L-γ-glutamylsulphamethoxazole resulted in higher total sulphamethoxazole concentrations in the kidney, but did not lead to an increase in released (unconjugated) sulphamethoxazole levels. In contrast, no kidney-selective distribution was observed for L-γ-glutamylsulphamethizole. Markedly increased kidney distribution was observed for both N-acetyl-L-γ-glutamyl-p-nitroaniline and N-acetyl-L-γ-glutamylsulpha-methoxazole and the liver and lung concentrations were correspondingly reduced in comparison with parent drug dosing. Use of the N-acetyl-L-γ-glutamyl-p-nitroaniline conjugate increased the concentration of p-nitroaniline in the kidney to the same extent as did L-γ-glutamyl-p-nitroaniline. In conclusion, N-acetyl-L-γ-glutamyl derivatization of certain compounds seems to be useful for kidney-specific ***drug delivery and preliminary data suggests that lipophilic drugs are better substrates than hydrophilic compounds. Results related to the selectivity of tissue distribution of the derivatives and species differences are discussed.