title: Renal targeting of captopril selectively enhances the intrarenal over the systemic effects of ACE inhibition in rats.
abstract: 1 In previous studies on the renal targeting of the ACE inhibitor captopril, we demonstrated that a 6 fold increased concentration of this drug could be obtained in the kidney after conjugation to the low-molecular-weight protein lysozyme. In this study, we investigated in unrestrained rats whether systemic administration of captopril-lysozyme also results in an enhanced effect on renal parameters, relative to the systemic effects. 2 Renal effects: intravenous infusion of captopril-lysozyme for 6 h resulted in a more pronounced increment of renal blood flow (31+/-2% vs 17+/-4% at 0.5 mg kg(-1) 6h(-1), P<0.01) and an approximately 5 fold enhanced natriuresis (167+/-17% vs 36+/-7% at 1 mg kg(-1) 6 h(-1), P<0.001) in comparison with equimolar amounts of captopril as a free drug. In correspondence with these findings, renal ACE inhibition was potentiated approximately 5 fold (-50+/-4% vs -22+/-3% at 1 mg kg(-1) 6 h(-1), P<0.001). 3 Systemic effects: conjugated captopril did not affect blood pressure in dosages up to 5 mg kg(-1) 6 h(-1). This effect coincided with a less pronounced inhibition of the pressor response to intravenously administered angiotensin I (-12+/-3% vs -66+/-5% at 1 mg kg(-1) 6 h(-1), P<0.001), and a markedly attenuated plasma ACE inhibition (-19+/-2% vs -37+/-3% at 1 mg kg(-1) 6 h(-1), P<0.001) compared to an equivalent dose of free captopril. 4 An experiment of continued intravenous administration of captopril-lysozyme for 7 days in nephrotic syndrome demonstrated that the conjugate is also active in renal disease: the antiproteinuric response was substantially augmented (-67+/-5% vs -15+/-7% at 4 mg kg(-1) 24 h(-1), P<0.001) compared to the free drug, in the absence of blood pressure reduction. 5 These data demonstrate that intravenous administration of a captopril-lysozyme conjugate leads to more selective renal ACE inhibition and enhanced renal effects as well as less systemic effects compared to captopril itself.
authors.affiliation: Department of Pharmacokinetics and Drug Delivery, University of Groningen, The Netherlands. R.F.G.Haverdings@farm.rug.nl
authors.forename: R Folgert G
authors.initials: RF
authors.lastname: Haverdings
authors.forename: Marijke
authors.initials: M
authors.lastname: Haas
authors.forename: Gerjan
authors.initials: G
authors.lastname: Navis
authors.forename: Anne-Miek
authors.initials: AM
authors.lastname: Van Loenen-Weemaes
authors.forename: Dirk K F
authors.initials: DK
authors.lastname: Meijer
authors.forename: Dick
authors.initials: D
authors.lastname: De Zeeuw
authors.forename: Frits
authors.initials: F
authors.lastname: Moolenaar
mesh_terms: D000803:Angiotensin I / Q000187:drug effects; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002216:Captopril / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin; D004337:Drug Carriers; D007150:Immunohistochemistry; D007275:Injections, Intravenous; D007668:Kidney / Q000098:blood supply / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D009113:Muramidase; D009404:Nephrotic Syndrome / Q000139:chemically induced / Q000188:drug therapy; D051381:Rats; D017208:Rats, Wistar; D012039:Regional Blood Flow
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D004337:Drug Carriers; D004317:Doxorubicin; D000803:Angiotensin I; D002216:Captopril; D009113:Muramidase