POTENTIALS AND LIMITATIONS OF THE LOW-MOLECULAR-WEIGHT PROTEIN LYSOZYME AS A CARRIER FOR RENAL DRUG TARGETING

Abstract

Selective targeting of drugs to the kidney may enable an increasedrenal effectiveness combined with a reduction of extrarenal toxicity. Intrarenaldelivery to the proximal tubular cell can be achieved using lowmolecular-weightproteins, such as lysozyme. Administration of high dosages of lysozyme, requiredto study the effects of such conjugates in vivo,however, is restricted since a partial escape of the renal reabsorption andthe occurrence of unwanted effects on systemic blood pressure and renal functionmay occur. The purpose of this study was to investigate the optimal parenteraladministration schedule and the maximum dose of lysozyme, providing the mostoptimal tubular reabsorption and at the same time a minimal effect on bloodpressure and renal hemodynamics, comparing continuous infusion of lysozymewith single dose injections. Urinary lysozyme excretion increased dose-dependently,both during continuous infusion and intravenous bolus injections. However,this loss of intact lysozyme into the urine was much higher after 3 injectionsof in total 250 mg.kg−1.6 h−1(51.8±3.7% of the dose) compared to the same dose administered by continuousinfusion (11.7±2.4%, P<0.001).Continuous infusion of lysozyme up to 1000 mg.kg−1in 6 hours had no effect on systemic blood pressure, whereas a bolus injectionof lysozyme (167 mg.kg−1) resulted in reversibleblood pressure lowering of 52.2±2.2% (P<0.001).A dose-dependent decline of the glomerular filtration rate was observed atdosages of lysozyme higher than 100 mg.kg−1.6h−1, with a maximal reduction of 53.0±3.7%after infusion of 1000 mg.kg−1.6 h−1.Effective renal plasma flow was less affected and only lowered statisticallysignificant at dosages of 500 (–12.6±3.3%, P<0.05)to 1000 mg.kg−1.6 h−1(–17.2±3.9%, P<0.01). Weconclude that bolus injections of lysozyme should not be used for renal targetingpurposes since it results in considerable tubular loss of lysozyme in theurine as well as cardiovascular side effects. In contrast, continuous infusionof lysozyme using dosages sufficient for renal drug targeting (maximally 15mg.kg−1.h−1)only has minimal effects on blood pressure and renal hemodynamics, with aminimal urinary lysozyme loss as well.