title: Targeting of captopril to the kidney reduces renal angiotensin-converting enzyme activity without affecting systemic blood pressure.
abstract: We have synthesized a prodrug of the angiotensin-converting enzyme (ACE) inhibitor captopril by coupling this drug covalently to the low molecular weight protein (LMWP) lysozyme. Such drug-LMWP conjugates can be used for renal drug delivery, since LMWPs accumulate specifically in the proximal tubular cells of the kidney. In the present study, we compared the effects of captopril-lysozyme and free captopril in male Wistar rats. ACE activity in plasma and the kidney was measured after intravenous bolus injection of either the captopril-lysozyme conjugate (33 mg. kg(-1), corresponding to 0.2 mg. kg(-1) captopril) or equivalent dosages of free captopril and lysozyme. The administration of the captopril-lysozyme conjugate resulted in less plasma ACE inhibition and a longer-lasting renal ACE inhibition compared with the free drug. Effects on blood pressure and natriuresis were studied during intravenous infusion of captopril-lysozyme (275 mg. kg(-1). 6 h(-1) conjugate, corresponding to 5 mg. kg(-1). 6 h(-1) captopril) or an equimolar dosage of free captopril. Captopril-lysozyme did not affect systemic blood pressure, whereas free captopril lowered blood pressure significantly (-23 +/- 32% versus control after 6 h). Captopril-lysozyme increased natriuresis about 3-fold compared with control levels (260 +/- 32% after 6 h), whereas free captopril treatment resulted in a reduced sodium excretion (26 +/- 12%). Furthermore, captopril at a lower dose, which only moderately lowered blood pressure, showed an increased sodium excretion. We conclude that renal delivery of captopril using captopril-lysozyme results in reduced systemic activity and increased kidney-specific activity of the targeted drug.
authors.affiliation: Department of Pharmacokinetics and Drug Delivery, Groningen University Institute for Drug Exploration, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands. r.j.kok@farm.rug.nl
authors.forename: R J
authors.initials: RJ
authors.lastname: Kok
authors.forename: R F G
authors.initials: RF
authors.lastname: Haverdings
authors.forename: F
authors.initials: F
authors.lastname: Grijpstra
authors.forename: J
authors.initials: J
authors.lastname: Koiter
authors.forename: F
authors.initials: F
authors.lastname: Moolenaar
authors.forename: D
authors.initials: D
authors.lastname: de Zeeuw
authors.forename: D K F
authors.initials: DK
authors.lastname: Meijer
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects* / Q000502:physiology; D002216:Captopril / Q000008:administration & dosage*; D016503:Drug Delivery Systems / Q000379:methods / Q000706:statistics & numerical data; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D007262:Infusions, Intravenous; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology*; D008297:Male; D009113:Muramidase / Q000008:administration & dosage; D011355:Prodrugs / Q000008:administration & dosage; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D011355:Prodrugs; D002216:Captopril; D009113:Muramidase