title: Drug delivery to the kidneys and the bladder with the low molecular weight protein lysozyme.
abstract: The low molecular weight protein (LMWP) lysozyme is a suitable drug carrier for renal drug targeting. When the tubular reabsorption of a LMWP can be prevented, the protein will be excreted in the urine. In this way, lysozyme (LZM) conjugates might also be used as carriers for targeting to the urinary tract. Since positive domains on the protein surface are important for the interaction with the tubular uptake-receptor, we studied the urinary excretion of a drug-LZM conjugate with and without positive charge on the LMWP. We synthesized two conjugates with the fluorescent compound fluorescein. A positively charged conjugate was obtained by reacting fluorescein isothiocyanate (FITC) with LZM at a 1:1 molar to molar ratio; this conjugate contained six free primary aminogroups. The conjugate without positively charged groups was obtained by reacting the remaining free primary aminogroups of the FITC-LZM with succinic anhydride (Suc). The Suc-FITC-LZM contained only 0.2 free primary aminogroups per molecule. We studied the pharmacokinetics of the conjugates in freely moving Wistar rats. The FITC-LZM conjugate was excreted intactly into the urine for 29 +/- 4% of the injected dose. The Suc-FITC-LZM was excreted into the urine intactly for 45 +/- 4%. These data indicate that the excretion of a drug-LMWP conjugate into the urine can be increased by decreasing the positive charge on the carrier surface. Such a carrier may be an attractive candidate for drug targeting to the bladder.
authors.affiliation: Department of Pharmacokinetics and Drug Delivery, University of Groningen, The Netherlands. rj.kok@farm.rug.nl
authors.forename: R J
authors.initials: RJ
authors.lastname: Kok
authors.forename: M
authors.initials: M
authors.lastname: Haas
authors.forename: F
authors.initials: F
authors.lastname: Moolenaar
authors.forename: D
authors.initials: D
authors.lastname: de Zeeuw
authors.forename: D K
authors.initials: DK
authors.lastname: Meijer
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000652:urine; D004337:Drug Carriers; D016503:Drug Delivery Systems; D016650:Fluorescein-5-isothiocyanate / Q000008:administration & dosage / Q000493:pharmacokinetics; D005456:Fluorescent Dyes / Q000008:administration & dosage / Q000493:pharmacokinetics; D007262:Infusions, Intravenous; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009113:Muramidase / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000652:urine; D051381:Rats; D017208:Rats, Wistar; D013387:Succinic Anhydrides / Q000008:administration & dosage / Q000493:pharmacokinetics; D001743:Urinary Bladder / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000890:Anti-Infective Agents; D004337:Drug Carriers; D005456:Fluorescent Dyes; D013387:Succinic Anhydrides; C031801:succinic anhydride; D009113:Muramidase; D016650:Fluorescein-5-isothiocyanate