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Pharmaceutical Research

, Volume 10, Issue 7, pp 963–969 | Cite as

Low Molecular Weight Proteins as Carriers for Renal Drug Targeting: Naproxen Coupled to Lysozyme via the Spacer L-Lactic Acid

  • Eric J. F. Franssen
  • Frits Moolenaar
  • Dick de Zeeuw
  • Dirk K. F. Meijer
Article

Abstract

Low molecular weight proteins (LMWPs) are potential carriers for targeting drugs to the kidney. To test whether ester bonds are suitable for the reversible drug conjugation, the antiinflammatory drug naproxen (Nap) was conjugated to the LMWP lysozyme (LYSO) via an ester bond using an L-lactic acid spacer (Nap-lact-LYSO, 1:1:1). The distribution and degradation of the conjugate in rats were compared to those of an equimolar mixture of free drug and LMWP and of a directly coupled conjugate without spacer (Nap-LYSO). The plasma clearance of Nap-lact-LYSO closely resembled that of Nap-LYSO and LYSO itself. Its major accumulation site appeared to be the kidney as demonstrated by extracorporal -γ-camera counting of the LMWP. Renally released naproxen was excreted in the urine as 6-desmethyl-naproxen-sulfate (6-DMN-S). Apparently the kidneys represent the main sites of demethylation and sulfation after administration of the LMWP-coupled drug. In addition, the renal excretion of naproxen (including its metabolites) was significantly delayed and sustained as compared to that after injection of uncoupled naproxen. Using the L-lactic acid spacer LMWP conjugation, the renal selectivity of Nap was increased 5.6 ± 0.41-fold. Additional in vitro studies with Nap-lact-LYSO revealed that renal generation of the parent drug coincided with formation of low molecular weight catabolites, mainly as naproxen-L-lactic acid-lysine (Nap-lact-Lys). This indicated that in vitro the rate of cleavage of the ester bond is significantly slower than digestion of the carrier backbone itself. It is concluded that for drugs with free carboxyl groups the coupling to LMWPs via α-hydroxy acids can result in renal-specific delivery and endorenal drug release.

drug targeting low molecular weight proteins carrier naproxen spacer engineering renal lysosomes L-lactic acid 

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Copyright information

© Plenum Publishing Corporation 1993

Authors and Affiliations

  • Eric J. F. Franssen
    • 1
  • Frits Moolenaar
    • 1
  • Dick de Zeeuw
    • 2
  • Dirk K. F. Meijer
    • 1
  1. 1.Department of Pharmacology and PharmacotherapyUniversity Center for PharmacyThe Netherlands
  2. 2.Department of Internal Medicine, Division of NephrologyUniversity HospitalThe Netherlands

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