Effect of gentamicin on pharmacokinetics of lysozyme in rats: interaction between megalin substrates in the kidney.
To investigate the pharmacokinetic interaction between substrates of megalin, a 600-kDa endocytic receptor abundantly expressed in the renal proximal tubules, we examined the effect of gentamicin infusion on the pharmacokinetics of fluorescein isothiocyanate (FITC)-lysozyme in rats. Infusion of gentamicin did not affect the plasma concentration-time profile of FITC-lysozyme. On the other hand, gentamicin significantly decreased the accumulation of FITC-lysozyme in the renal cortex and medulla, whereas the accumulation in the renal papilla, liver, brain and lung was not changed. Urinary excretion of FITC-lysozyme was increased by gentamicin, whereas there was no change in the biliary excretion of FITC-lysozyme or its degradation products. Gentamicin infusion had little influence on the ATP content in the renal cortex and urinary excretion of glucose, indicating that nephrotoxicity is not induced by short-term infusion of gentamicin. These findings suggest that lysozyme and gentamicin interact with each other in their reabsorption processes in the renal proximal tubules, probably by competing for their binding to megalin expressed in the apical membrane of the renal proximal tubules.
Nagai
Junya
J
Department of Pharmaceutics and Therapeutics, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan.
Katsube
Takayuki
T
Murakami
Teruo
T
Takano
Mikihisa
M
D000818:Animals; D001921:Brain / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D016650:Fluorescein-5-isothiocyanate / Q000737:chemistry; D005456:Fluorescent Dyes / Q000737:chemistry; D005839:Gentamicins / Q000008:administration & dosage / Q000494:pharmacology*; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000378:metabolism*; D008168:Lung / Q000378:metabolism; D008297:Male; D009113:Muramidase / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D014018:Tissue Distribution
D005456:Fluorescent Dyes; D005839:Gentamicins; D026561:Low Density Lipoprotein Receptor-Related Protein-2; D009113:Muramidase; D016650:Fluorescein-5-isothiocyanate