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Drug Metabolism and Disposition Fast Forward
First published on January 26, 2005; DOI: 10.1124/dmd.104.002808

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*Compound via MeSH
*Substance via MeSH
Hazardous Substances DB
*CAPTOPRIL
*DOXORUBICIN


Received for publication November 1, 2004.
Revised January 25, 2005.
Accepted for publication January 25, 2005.

RENAL-SELECTIVE DELIVERY AND ACE INHIBITION BY SUBCUTANEOUSLY ADMINISTERED CAPTOPRIL-LYSOZYME

Jai Prakash 1, Annemiek M van Loenen-Weemaes 1, Marijke Haas 2, Johannes H Proost 1, Dirk KF Meijer 1, Frits Moolenaar 1, Klaas Poelstra 1, Robbert J Kok 1*

1 Groningen University Institute for Drug Exploration 2 BioMaDe Technology Foundation

* Address correspondence to: E-mail: r.j.kok{at}farm.rug.nl

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 HPLC analysis and by ACE activity measurements. Lysozyme was absorbed gradually and completely from the subcutaneous injection site within 24 hours and accumulated specifically in the kidneys. After subcutaneous injection of the captopril-lysozyme conjugate, higher renal captopril levels and lower captopril-lysozyme levels in urine indicated the improved renal accumulation in comparison to intravenous administration of the conjugate, as well as its stability at the injection site. After both treatments captopril-lysozyme conjugate effectuated renal ACE inhibition, while 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.


Key words: drug delivery, drug disposition, drug targeting, pharmacokinetics, prodrugs, renal disposition, targeted delivery


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