Renal targeting of captopril selectively enhances the intrarenal over the systemic effects of ACE inhibition in rats

Abstract

1 In previous studies on the renal targeting of the ACE inhibitor captopril, we demonstrated that a 6 fold increased concentration of this drug could be obtained in the kidney after conjugation to the low-molecular-weight protein lysozyme. In this study, we investigated in unrestrained rats whether systemic administration of captopril ± lysozyme also results in an enhanced e ect on renal parameters, relative to the systemic e ects.2 Renal e ects: intravenous infusion of captopril ± lysozyme for 6 h resulted in a more pronounced increment of renal blood¯ow (31+2% vs 17+4% at 0.5 mg kg 71 6h 71 , P50.01) and an approximately 5 fold enhanced natriuresis (167+17% vs 36+7% at 1 mg kg 71 6 h 71 , P50.001) in comparison with equimolar amounts of captopril as a free drug. In correspondence with these ®ndings, renal ACE inhibition was potentiated approximately 5 fold (750+4% vs 722+3% at 1 mg kg 71 6 h 71 , P50.001).3 Systemic e ects: conjugated captopril did not a ect blood pressure in dosages up to 5 mg kg 71 6 h 71 . This e ect coincided with a less pronounced inhibition of the pressor response to intravenously administered angiotensin I (712+3% vs 766+5% at 1 mg kg 71 6 h 71 , P50.001), and a markedly attenuated plasma ACE inhibition (719+2% vs 737+3% at 1 mg kg 71 6 h 71 , P50.001) compared to an equivalent dose of free captopril. 4 An experiment of continued intravenous administration of captopril ± lysozyme for 7 days in nephrotic syndrome demonstrated that the conjugate is also active in renal disease: the antiproteinuric response was substantially augmented (767+5% vs 715+7% at 4 mg kg 71 24 h 71 , P50.001) compared to the free drug, in the absence of blood pressure reduction. 5 These data demonstrate that intravenous administration of a captopril ± lysozyme conjugate leads to more selective renal ACE inhibition and enhanced renal e ects as well as less systemic e ects compared to captopril itself.

Kidney–targeted drug delivery systems

“…The ACE inhibitor captopril has also been conjugated with lysozyme via a disulfide bond and using succinimidyloxycarbonyl- α -methyl- α -(2-pyridyldithio) toluene (SMPT) as a linker 18,19 . Research showed captopril could be released from the conjugate either enzymatically by β -lyase and/or non-enzymatically by thiol-disulfide exchange with endogenous thiols.…”

Low Molecular Weight Hydroxyethyl Chitosan-Prednisolone Conjugate for Renal Targeting Therapy: Synthesis, Characterization and In Vivo Studies

“…The renal proximal tubular cell, triggered by long-term exposure to proteins, is believed to play a pivotal role in the cascade of pathophysiological processes towards end-stage renal failure (ESKD) 1, which is irreversible and permanent. As the pathogenic condition becomes worse, renal replacement therapy (RRT), such as dialysis or renal transplantation, has to be applied to sustain the lives of patients.…”