title: Influences of dosage regimen and co-administration of low-molecular weight proteins and basic peptides on renal accumulation of arbekacin in mice.
abstract: OBJECTIVE
  The objectives of this study were to characterize renal accumulation of arbekacin, an aminoglycoside antibiotic for treatment of infections with methicillin-resistant Staphylococcus aureus, and to modulate renal uptake of arbekacin, leading to prevention of arbekacin-induced nephrotoxicity.
  
  
  METHODS
  In vivo renal uptake studies were performed using mice. Renal concentrations of arbekacin after a bolus intravenous administration at various doses were analysed by HPLC. In addition, renal concentrations were investigated 24 h after an injection of arbekacin alone or in combination with low-molecular weight proteins and basic peptides.
  
  
  RESULTS
  When administered by bolus injection at various doses, renal accumulation of arbekacin showed saturation kinetics with increasing dose. Renal concentration of arbekacin after a bolus administration remained constant from 4 to 24 h and subsequently decreased by a first-order process with a half-life of 42.7 h. The influences of three dosage regimens (a single injection of 4 mg/kg, two injections of 2 mg/kg and three injections of 1.33 mg/kg) were investigated. A single injection resulted in lower renal level of arbekacin than the multiple administrations. Co-administration of cytochrome c, lysozyme and N-WASP181-200 decreased renal accumulation of arbekacin in a dose-dependent manner. N-W(N1n), N-W(N1n,I2i,S3s) and N-W(N1n,K20k), in which the N- and/or C-terminal regions of N-WASP181-200 were substituted by one to three D-isomers, more potently decreased renal arbekacin accumulation than N-WASP181-200.
  
  
  CONCLUSIONS
  These data may be useful for prevention of arbekacin-induced nephrotoxicity owing to reduction of renal accumulation of the aminoglycoside.
authors.affiliation: Department of Pharmaceutics and Therapeutics, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Murakami
authors.forename: Junya
authors.initials: J
authors.lastname: Nagai
authors.forename: Kenji
authors.initials: K
authors.lastname: Fujii
authors.forename: Ryoko
authors.initials: R
authors.lastname: Yumoto
authors.forename: Mikihisa
authors.initials: M
authors.lastname: Takano
mesh_terms: D000617:Aminoglycosides / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D000818:Animals; D003982:Dibekacin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008970:Molecular Weight; D010455:Peptides / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D011506:Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics
chemical_list: D000617:Aminoglycosides; D010455:Peptides; D011506:Proteins; D003982:Dibekacin; C031986:arbekacin