Molecular-targeted approaches to reduce renal accumulation of nephrotoxic drugs.
BACKGROUND
Nephrotoxicity limits the clinical use of some antibiotics, cancer chemotherapeutics and diagnostic agents. Some nephrotoxic drugs are highly accumulated in the kidney via specific transport systems expressed in renal proximal tubular cells. The concentrated and retained accumulation often leads to nephrotoxicity. Therefore, the molecular-targeted blockade of renal uptake of nephrotoxic drugs is considered to be one of the promising strategies for the prevention of the drug-induced nephrotoxicity.


METHODS
This review focuses on recent approaches toward prevention of renal accumulation of nephrotoxic drugs, especially aminoglycoside antibiotics and radiolabeled somatostatin analogs, based on the molecular mechanisms underlying cellular uptake in the kidney.


RESULTS
In renal proximal tubular cells, aminoglycosides and radiolabeled somatostatin analogs are taken up via endocytosis mediated by megalin and cubilin, the major endocytic receptors responsible for reabsorption of proteins and peptides in the glomerular filtrate. Some ligands for these receptors can decrease renal accumulation of aminoglycosides and radiolabeled somatostatin analogs under in vivo conditions.


CONCLUSIONS
Co-administration of agents with which to inhibit the binding of nephrotoxic drugs to receptor(s) responsible for the endocytic processes in renal proximal tubular cells might reduce the incidence of nephrotoxicity.
Department of Pharmaceutics and Therapeutics, Hiroshima University, Graduate School of Biomedical Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan.
Junya
J
Nagai
Mikihisa
M
Takano
D000617:Aminoglycosides / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000900:Anti-Bacterial Agents / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D001692:Biological Transport; D016503:Drug Delivery Systems; D064420:Drug-Related Side Effects and Adverse Reactions; D004705:Endocytosis / Q000187:drug effects; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000378:metabolism; D008024:Ligands; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010455:Peptides / Q000378:metabolism / Q000494:pharmacology; D004364:Pharmaceutical Preparations / Q000378:metabolism; D051381:Rats; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000378:metabolism
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D008024:Ligands; D026561:Low Density Lipoprotein Receptor-Related Protein-2; D010455:Peptides; D004364:Pharmaceutical Preparations; D013004:Somatostatin