Low molecular weight proteins as carriers for renal drug targeting : naproxen-lysozyme

Low molecular weight proteins (LMWPs), such as lysozyme, may be suitable carriers to target drugs to the kidney. In this study the antiinflammatory drug naproxen was covalently bound to lysozyme (1:1). Pharmacokinetics of the conjugate, naproxen-lysozyme (nap-LYSO), were compared to that of an equimolar mixture of uncoupled naproxen with lysozyme in freely moving rats. Similar plasma kinetics and organ distribution for native lysozyme and the drug conjugate were observed (Clp = 1.2 and 1.1 ml/min; t1/2,beta = 85 and 75 min, respectively). In case of the uncoupled naproxen-lysozyme mixture, a monoexponential plasma disappearance of naproxen with a t1/2 of 2.8 hr was observed, coinciding with urinary excretion of naproxen metabolites (mainly 6-desmethylnaproxen sulfate; 6-DMN-S) between 2 and 8 hr after injection. Urinary recovery of total metabolites was 59% of the naproxen dose. In contrast, after injection of covalently bound naproxen, plasma levels of the parent drug were below the detection level, whereas naproxen was recovered as 6-DMN-S in urine over a period from 4 to 30 hr. However, only 8% of the administered dose was recovered as 6-DMN-S in urine, whereas 50% of the dose was recovered as naproxen metabolites in feces. Incubation experiments using purified renal tubular lysosomal lysates revealed that naproxen-lysozyme degradation ultimately results in a stable naproxen amino acid catabolite, naproxen-lysine (nap-lys). Hepatic uptake and biliary excretion of this catabolyte were demonstrated in isolated perfused rat livers. Further, an equipotent pharmacological activity relative to parent naproxen was observed.