RT Journal Article SR Electronic T1 Targeting of Captopril to the Kidney Reduces Renal Angiotensin-Converting Enzyme Activity without Affecting Systemic Blood Pressure JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 1139 OP 1143 DO 10.1124/jpet.301.3.1139 VO 301 IS 3 A1 R. J. Kok A1 R. F. G. Haverdings A1 F. Grijpstra A1 J. Koiter A1 F. Moolenaar A1 D. de Zeeuw A1 D. K. F. Meijer YR 2002 UL http://jpet.aspetjournals.org/content/301/3/1139.abstract AB 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. The American Society for Pharmacology and Experimental Therapeutics