Potentials and limitations of the low-molecular-weight protein lysozyme as a carrier for renal drug targeting.
Selective targeting of drugs to the kidney may enable an increased renal effectiveness combined with a reduction of extrarenal toxicity. Intrarenal delivery to the proximal tubular cell can be achieved using low-molecular-weight proteins, such as lysozyme. Administration of high dosages of lysozyme, required to study the effects of such conjugates in vivo, however, is restricted since a partial escape of the renal reabsorption and the occurrence of unwanted effects on systemic blood pressure and renal function may occur. The purpose of this study was to investigate the optimal parenteral administration schedule and the maximum dose of lysozyme, providing the most optimal tubular reabsorption and at the same time a minimal effect on blood pressure and renal hemodynamics, comparing continuous infusion of lysozyme with 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 injections of in total 250 mg x kg(-1) x 6 h(-1) (51.8+/-3.7% of the dose) compared to the same dose administered by continuous infusion (11.7+/-2.4%, P < 0.001). Continuous infusion of lysozyme up to 1000 mg x kg(-1) in 6 hours had no effect on systemic blood pressure, whereas a bolus injection of lysozyme (167 mg x kg(-1)) resulted in reversible blood pressure lowering of 52.2+/-2.2% (P<0.001). A dose-dependent decline of the glomerular filtration rate was observed at dosages of lysozyme higher than 100 mg x kg(-1) x 6 h(-1), with a maximal reduction of 53.0+/-3.7% after infusion of 1000 mg x kg(-1) x 6 h(-1). Effective renal plasma flow was less affected and only lowered statistically significant at dosages of 500 (-12.6+/-3.3%, P<0.05) to 1000 mg x kg(-1) x 6 h(-1) (-17.2+/-3.9%, P<0.01). We conclude that bolus injections of lysozyme should not be used for renal targeting purposes since it results in considerable tubular loss of lysozyme in the urine as well as cardiovascular side effects. In contrast, continuous infusion of lysozyme using dosages sufficient for renal drug targeting (maximally 15 mg x kg(-1) x h(-1)) only has minimal effects on blood pressure and renal hemodynamics, with a minimal urinary lysozyme loss as well.
Haverdings
R F
RF
Department of Pharmacokinetics and Drug Delivery, University Centre for Pharmacy, Groningen University Institute for Drug Exploration (GUIDE), University of Groningen, The Netherlands. R.F.G.Haverdings@farm.rug.nl
Haas
M
M
Greupink
A R
AR
de Vries
P A
PA
Moolenaar
F
F
de Zeeuw
D
D
Meijer
D K
DK
D000818:Animals; D000890:Anti-Infective Agents / Q000008:administration & dosage*; D001794:Blood Pressure / Q000187:drug effects*; D004337:Drug Carriers; D007263:Infusions, Parenteral; D007674:Kidney Diseases / Q000188:drug therapy; D008297:Male; D020714:Maximum Tolerated Dose; D009113:Muramidase / Q000008:administration & dosage* / Q000652:urine; D051381:Rats; D017208:Rats, Wistar; D012079:Renal Circulation / Q000187:drug effects*
D000890:Anti-Infective Agents; D004337:Drug Carriers; D009113:Muramidase