Drug-targeting to the kidney: renal delivery and degradation of a naproxen-lysozyme conjugate in vivo.
A renal-specific controlled release of an active drug may enable a reduction of the required dose and may provide a reduction of extra-renal toxicity. To achieve renal specific targeting of the NSAID naproxen, the low-molecular-weight protein (LMWP) lysozyme was employed as carrier since it is mainly taken up and catabolized in the proximal tubules of the kidney. A conjugate was synthesized with an average coupling degree of 2 mol naproxen per 1 mol lysozyme in which the drug was directly coupled to the protein via a peptide bond. First, we investigated whether naproxen conjugation affects the renal disposition of lysozyme. As native lysozyme, the conjugate was predominantly and rapidly (within 20 min) taken up by the kidney. The subsequent decrease in renal content reflecting the renal degradation of the conjugated lysozyme molecules appeared also to be similar to that of native lysozyme with a half life of four hours. Second, the effect of lysozyme conjugation on the body distribution of naproxen was studied. An important observation with regard to the aimed reduction in extra-renal side effects was that no detectable amounts of free naproxen were present in the plasma after administration of conjugate. Conjugation of naproxen to lysozyme resulted in a pronounced (70-fold) increase of naproxen accumulation in the kidney. In agreement with the protein disposition study, the conjugate was rapidly taken up by the kidney and subsequently degraded. In conclusion, renal selective targeting of the NSAID naproxen can be obtained by conjugation with the LMWP lysozyme. This concept of drug delivery to the kidney has the potential to improve drug efficacy and safety.
Haas
M
M
Groningen Institute for Drug Studies (GIDS), The Netherlands.
Kluppel
A C
AC
Wartna
E S
ES
Moolenaar
F
F
Meijer
D K
DK
de Jong
P E
PE
de Zeeuw
D
D
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D015232:Dinoprostone / Q000652:urine; D005260:Female; D007457:Iodine Radioisotopes; D007674:Kidney Diseases / Q000188:drug therapy*; D007687:Kidney Tubules, Proximal / Q000378:metabolism; D007700:Kinetics; D008297:Male; D009113:Muramidase / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D009288:Naproxen / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution
D000894:Anti-Inflammatory Agents, Non-Steroidal; D007457:Iodine Radioisotopes; D009288:Naproxen; D009113:Muramidase; D015232:Dinoprostone