Drug-targeting to the kidney: Renal delivery and degradation of a naproxen-lysozyme conjugate in vivo

Abstract

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.

Renal-Selective Delivery and Angiotensin-Converting Enzyme Inhibition by Subcutaneously Administered Captopril-Lysozyme

“…In the kidneys, LMWPs are freely filtered through the glomerulus and reabsorbed by receptormediated endocytosis into the proximal tubular cells, and subsequently catabolized intralysosomally into small peptides and single amino acids (Christensen and Nielsen 1991;Christensen and Birn 2001). Our studies demonstrated that drug-lysozyme conjugates selectively accumulated in the kidneys after intravenous administration (Haas et al, 1997;Kok et al, 1999). However, it is not feasible to administer such conjugates intravenously for long-term therapy in animal or human subjects.…”

Renal targeting of a non-steroidal anti-inflammatory drug: effects on renal prostaglandin synthesis in the rat

“…Naproxen-lysozyme conjugate was synthesized as described previously [7]. Briefly, naproxen was activated with N-hydroxysuccinimide [23].…”

“…We previously showed that the nonsteroidal anti-inflammatory drug (NSAID) naproxen could be targeted to the kidney by coupling it to the LMWP lysozyme [6]. Conjugation to lysozyme resulted in a 70-fold increase of naproxen accumulation in the kidney with a subsequent gradual reduction in amount in time [7]. Of note, it was not the parent drug naproxen that was released from the conjugate but the more hydrophilic metabolite naproxen-lysine.…”

Kinetic release of triptolide after injection of renal‐targeting 14‐succinyl triptolide‐lysozyme in a rat kidney study by liquid chromatography/mass spectrometry

“…To address these issues with the potential eventual clinical applications, we designed and prepared the renaltargeting 14-succinyl triptolide-lysozyme (TPS-LZM, Fig. 1, III) (Fransen et al, 1991;Haas et al, 1993Haas et al, , 1997Zheng et al, 2007). Although many studies have been carried out on the immunosuppressant effects of TP and its derivatives in renal diseases, most of them have focused on pharmacological features.…”