Renal-selective delivery and angiotensin-converting enzyme inhibition by subcutaneously administered captopril-lysozyme.
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 captopril-lysozyme 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.
Prakash
Jai
J
Department of Pharmacokinetics and Drug Delivery, University of Groningen, The Netherlands.
van Loenen-Weemaes
Annemiek M
AM
Haas
Marijke
M
Proost
Johannes H
JH
Meijer
Dirk K F
DK
Moolenaar
Frits
F
Poelstra
Klaas
K
Kok
Robbert J
RJ
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology*; D000818:Animals; D000903:Antibiotics, Antineoplastic; D002216:Captopril / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000494:pharmacology*; D004317:Doxorubicin; D016503:Drug Delivery Systems; D007279:Injections, Subcutaneous; D007668:Kidney / Q000000981:diagnostic imaging / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D009113:Muramidase / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000494:pharmacology*; D009401:Nephrosis / Q000139:chemically induced / Q000378:metabolism; D011507:Proteinuria / Q000378:metabolism; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar
D000806:Angiotensin-Converting Enzyme Inhibitors; D000903:Antibiotics, Antineoplastic; D019275:Radiopharmaceuticals; D004317:Doxorubicin; D002216:Captopril; D009113:Muramidase