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Renal targeting of captopril using captopril-lysozyme conjugate enhances its antiproteinuric effect in adriamycin-induced nephrosis
Willemijn AKM Windt
Department of Clinical Pharmacology, Groningen University Institute for Drug Exploration (GUIDE), University Medical Centre Groningen, Groningen, The Netherlands, w.a.k.m.windt{at}med.umcg.nl
Jai Prakash
Department of Pharmacokinetics and Drug Delivery, University Centre for Pharmacy, University of Groningen, Groningen, The Netherlands
Robbert Jan Kok
Department of Pharmacokinetics and Drug Delivery, University Centre for Pharmacy, University of Groningen, Groningen, The Netherlands
Frits Moolenaar
Department of Pharmacokinetics and Drug Delivery, University Centre for Pharmacy, University of Groningen, Groningen, The Netherlands
C Alex Kluppel
Department of Clinical Pharmacology, Groningen University Institute for Drug Exploration (GUIDE), University Medical Centre Groningen, Groningen, The Netherlands
Dick de Zeeuw
Department of Clinical Pharmacology, Groningen University Institute for Drug Exploration (GUIDE), University Medical Centre Groningen, Groningen, The Netherlands
Richard PE van Dokkum
Department of Clinical Pharmacology, Groningen University Institute for Drug Exploration (GUIDE), University Medical Centre Groningen, Groningen, The Netherlands
Robert H Henning
Department of Clinical Pharmacology, Groningen University Institute for Drug Exploration (GUIDE), University Medical Centre Groningen, Groningen, The Netherlands
Introduction
High-sodium intake blunts the renoprotective efficacy of angiotensin-converting enzyme (ACE) inhibitors. We investigated whether targeting the drug to the kidneys may attenuate the inferior response to ACE inhibitor (ACE-I) under high-sodium conditions. The ACE-I, captopril, was coupled to the low molecular weight protein (LMWP) lysozyme, yielding captopril-lysozyme conjugates that accumulate specifically in the proximal tubular cells of the kidneys.We compared the antiproteinuric efficacy of captopril to that of the captopril-lysozyme conjugate in adriamycin-induced proteinuric rats fed with a high-sodium diet.
Materials and methods
Rats with adriamycin (single injection 2 mg/kg)-induced proteinuria were put on a high-sodium diet (HS; 3% NaCl). When stable proteinuria developed at 5.5 weeks, animals were assigned to the following subcutaneous treatments: (1) vehicle (n=7); (2) lysozyme (equivalent to the amount in conjugate) (n=7); (3) captopril (5 mg/kg/24 hours) (n=8); (4) captopril-lysozyme conjugate (captopril content equivalent to 1mg captopril/kg/24 hours) (n=7). Blood pressure and proteinuria were monitored. After 10 days of treatment the rats were sacrificed and kidneys and plasma were removed.
Results
Results are given as mean + S.E.M. After injection with adriamycin at t=0, stable proteinuria developed, amounting to 547+79 mg/24 hours at week 5.5. Subsequently, after seven and nine days of treatment, no reduction of proteinuria was observed in the captopril-treated group. In contrast, a significant reduction in proteinuria, amounting to 35+4% (day seven) and 25+2% (day nine), was observed in the captopril-lysozyme conjugate group (p<0.05 compared with the captopril group). In contrast, blood pressure was reduced in the captopril-treated group by 13.9+2.9 mmHg, while in the captopril-lysozyme treated group, an increase of 7.9+3.3 mmHg was found. Renal ACE activity was lowered by 30% in the captopril, as well as in the captopril-lysozyme conjugate treated group, compared with control. Furthermore, the ratio of kidney: plasma levels of captopril almost doubled as a consequence of coupling to lysozyme.
Conclusion
In proteinuric rats fed with a high-sodium diet, captopril induced a reduction in blood pressure without an effect on proteinuria. In contrast, renal targeting of a five times lower dose of the ACE-I with the captopril-lysozyme conjugate reduced proteinuria without reducing blood pressure. Therefore, renal targeting of ACE-I may be a promising strategy to optimise the therapeutic response of ACE-I.
Key Words: ACE-inhibition • renal targeting • proteinuria • low molecular weight protein • lysozyme
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Journal of Renin-Angiotensin-Aldosterone System, Vol. 5, No. 4,
197-202 (2004)
DOI: 10.3317/jraas.2004.040
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