Specific delivery of captopril to the kidney with the prodrug captopril-lysozyme.
Low-molecular-weight proteins (LMWPs) accumulate in the proximal tubular cells of the kidney, which makes these proteins interesting tools for renal drug targeting. We studied this approach using the LMWP lysozyme as a carrier for the angiotensin-converting enzyme inhibitor captopril. Captopril was conjugated to lysozyme via a disulfide bond. The pharmacokinetics of the captopril-lysozyme conjugate was studied in the rat. Only intact conjugate could be detected in the circulation. The total amount of captopril disulfides in the kidney was six times higher after administration of the conjugate than after the administration of an equivalent amount of free captopril. The conjugate was recovered in the urine partially as intact conjugate and partially as low-molecular-weight disulfides. The excretion of conjugate in the urine was not a consequence of the coupling of captopril to lysozyme because an equivalent bolus dose of native lysozyme was similarly excreted into the urine. By determination of the renal angiotensin-converting enzyme activity, we showed that the conjugate was degraded to the pharmacologically active captopril in vivo. We conclude that the coupling of captopril to the LMWP lysozyme results in increased captopril concentrations in the kidney and reduced captopril concentrations in the circulation.
Kok
R J
RJ
Department of Pharmacokinetics and Drug Delivery, Groningen Utrecht Institute for Drug Exploration, Groningen, the Netherlands.
Grijpstra
F
F
Walthuis
R B
RB
Moolenaar
F
F
de Zeeuw
D
D
Meijer
D K
DK
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000818:Animals; D002216:Captopril / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016503:Drug Delivery Systems; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D009113:Muramidase / Q000008:administration & dosage / Q000493:pharmacokinetics; D011355:Prodrugs / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
D000806:Angiotensin-Converting Enzyme Inhibitors; D011355:Prodrugs; D002216:Captopril; D009113:Muramidase