Targeting of Captopril to the Kidney Reduces Renal Angiotensin-Converting Enzyme Activity without Affecting Systemic Blood Pressure

Kok, RJ; Haverdings, Rene; Grijpstra, F.; Koiter, J.; Moolenaar, Frits; Zeeuw, de Dick; Meijer, Dirk K. F.

doi:10.1124/jpet.301.3.1139

Cited by 10 publications

(11 citation statements)

References 19 publications

(18 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These results are in accordance with those reported by Kok and colleagues, 33 who used lysozyme as the carrier. In their work, lysozyme-CAP exhibited enhanced kidney accumulation efficiency by 6-fold compared to free CAP.…”

Section: ■ Discussionsupporting

confidence: 95%

Peptide–Drug Conjugate Linked via a Disulfide Bond for Kidney Targeted Drug Delivery

et al. 2012

View full text Add to dashboard Cite

Chronic kidney disease (CKD) is a worldwide public health problem, and unfortunately, the therapeutic index of clinically available drugs is limited. Thus, there is a great need to exploit effective treatment strategies, and the carrier-drug approach is an attractive method to improve the kidney specificity of the therapeutic agents. The aim of this present study is to develop a peptide-drug conjugate for the kidney targeted delivery of angiotensin-converting enzyme (ACE) inhibitor captopril (CAP), since G3-C12 peptide (ANTPCGPYTHDCPVKR) could specifically accumulate in the kidney after intravenous injection. Therefore, FITC labeled G3-C12 peptide (G3-C12-FITC) and peptide-drug conjugate (G3-C12-CAP) with a disulfide bond which can be cleaved by reduced glutathione in the kidney were prepared by solid-phase peptide synthesis. The fluorescence imaging of G3-C12-FITC revealed that the labeled peptide specifically accumulated in the kidney soon after i.v. injection to mice, and the accumulation is due largely to the reabsorption of the peptide by the proximal renal tubule cells. Furthermore, in comparison with the corresponding nonconjugated form, a 2.7-fold increase in renal area under concentration-time curve produced by the conjugate was observed in mice. Interestingly, the CAP entirely released in the kidney even at 0.05 h postinjection through disulfide reduction. As a consequence, the in vivo renal ACE inhibition was significantly increased. In conclusion, these findings suggest the potential of G3-C12 peptide serving as a suitable candidate carrier for kidney-targeted drug delivery.

show abstract

Section: ■ Discussionsupporting

confidence: 95%

Peptide–Drug Conjugate Linked via a Disulfide Bond for Kidney Targeted Drug Delivery

et al. 2012

View full text Add to dashboard Cite

show abstract

“…Captopril is released in its active form inside proximal tubular cells of the kidney due to the high levels of glutathione present [48]. A later study demonstrated that the captopril-LZM conjugate caused a higher kidney specific activity of the drug while a lower systematic activity of the drug, hence suggesting the conjugate could be used to treat renal disease without affecting blood pressure [49].…”

Section: Other Protein Disulfide Drug Conjugatesmentioning

confidence: 99%

Reversible Covalent Chemistry in Drug Delivery

West

Otto

2005

CDDT

150

109

View full text Add to dashboard Cite

The targeting of drugs specifically to their sites of action is an important strategy for increasing drug efficacy. Chemists have come up with many elegant schemes that aim to convert drugs into magic bullets. This review focuses on the chemistry that underlies these schemes, with particular emphasis on two types of cleavable covalent bonds that are frequently used to link drugs to their various carriers: disulfide bonds and hydrazone bonds. These linkages have been used to release drugs under specific conditions; in the case of disulfides, cleavage is triggered by the mildly reducing environment found in intracellular fluids, and in the case of hydrazones, the acidic conditions that prevail in endosomes cause release of the drug. The applications of these chemistries in drug delivery are reviewed.

show abstract

“…The synthesis and characterization of captopril-lysozyme were performed as described elsewhere (Kok et al, 2002). Typically, lysozyme (100 mg, 7 mol) was dissolved in borate buffer (0.1 mM, pH 7.5) at a concentration of 20 mg/ml.…”

Section: Methodsmentioning

confidence: 99%

Renal-Selective Delivery and Angiotensin-Converting Enzyme Inhibition by Subcutaneously Administered Captopril-Lysozyme

et al. 2005

View full text Add to dashboard Cite

ABSTRACT:In previous studies, we have demonstrated that the low molecular weight protein lysozyme can be used as a renal-selective drug carrier for delivery of the angiotensin-converting enzyme (ACE) inhibitor captopril. Typically, such macromolecular drug-targeting preparations are administered intravenously. In the present study, we investigated the fate of captopril-lysozyme following subcutaneous administration, a convenient route for long-term treatment. The absorption from the subcutaneous injection site and renal uptake of lysozyme were determined by gamma scintigraphy in rats. Bioavailability, renal accumulation, and stability of the captopril-lysozyme conjugate were evaluated by high performance liquid chromatography analysis and by ACE activity measurements.Lysozyme was absorbed gradually and completely from the subcutaneous injection site within 24 h and accumulated specifically in kidneys. After subcutaneous injection of the captopril-lysozyme conjugate, higher renal captopril levels and lower captoprillysozyme levels in urine indicated the improved renal accumulation in comparison with intravenous administration of the conjugate, as well as its stability at the injection site. After both treatments, captopril-lysozyme conjugate effectuated renal ACE inhibition, whereas plasma ACE was not inhibited. In conclusion, our results demonstrate that we can use the subcutaneous route to administer drug delivery preparations like the captopril-lysozyme conjugate.

show abstract

Targeting of Captopril to the Kidney Reduces Renal Angiotensin-Converting Enzyme Activity without Affecting Systemic Blood Pressure

Cited by 10 publications

References 19 publications

Peptide–Drug Conjugate Linked via a Disulfide Bond for Kidney Targeted Drug Delivery

Peptide–Drug Conjugate Linked via a Disulfide Bond for Kidney Targeted Drug Delivery

Reversible Covalent Chemistry in Drug Delivery

Renal-Selective Delivery and Angiotensin-Converting Enzyme Inhibition by Subcutaneously Administered Captopril-Lysozyme

Contact Info

Product

Resources

About