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Research ArticleARTICLE

Specific Delivery of Captopril to the Kidney with the Prodrug Captopril-Lysozyme

R. J. Kok, F. Grijpstra, R. B. Walthuis, F. Moolenaar, D. de Zeeuw and D. K. F. Meijer
Journal of Pharmacology and Experimental Therapeutics January 1999, 288 (1) 281-285;
R. J. Kok
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F. Grijpstra
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R. B. Walthuis
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F. Moolenaar
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D. de Zeeuw
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D. K. F. Meijer
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Abstract

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.

Footnotes

  • Send reprint requests to: Dr. R. J. Kok, Groningen Utrecht Institute for Drug Exploration, Department of Pharmacokinetics and Drug Delivery, University Center for Pharmacy, A. Deusinglaan 1, 9713 AV Groningen, the Netherlands. E-mail:R.J.Kok{at}farm.rug.nl

  • ↵1 This work was supported by Dutch Organization for Scientific Research (NWO) Grant 902-21-151.

  • Abbreviations:
    ACE
    angiotensin-converting enzyme
    LMWP
    low-molecular-weight protein
    CAP
    captopril
    HPLC
    high-performance liquid chromatography
    LZM
    lysozyme
    SMPT
    succinimidyloxycarbonyl-α-methyl-α-(2-pyridyldithio)toluene
    TBP
    tributylphosphine
    • Received March 25, 1998.
    • Accepted August 16, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 288 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 288, Issue 1
1 Jan 1999
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Research ArticleARTICLE

Specific Delivery of Captopril to the Kidney with the Prodrug Captopril-Lysozyme

R. J. Kok, F. Grijpstra, R. B. Walthuis, F. Moolenaar, D. de Zeeuw and D. K. F. Meijer
Journal of Pharmacology and Experimental Therapeutics January 1, 1999, 288 (1) 281-285;

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Research ArticleARTICLE

Specific Delivery of Captopril to the Kidney with the Prodrug Captopril-Lysozyme

R. J. Kok, F. Grijpstra, R. B. Walthuis, F. Moolenaar, D. de Zeeuw and D. K. F. Meijer
Journal of Pharmacology and Experimental Therapeutics January 1, 1999, 288 (1) 281-285;
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