Influences of dosage regimen and co-administration of low-molecular weight proteins and basic peptides on renal accumulation of arbekacin in mice.
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.
Murakami
Sachiko
S
Department of Pharmaceutics and Therapeutics, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan.
Nagai
Junya
J
Fujii
Kenji
K
Yumoto
Ryoko
R
Takano
Mikihisa
M
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
D000617:Aminoglycosides; D010455:Peptides; D011506:Proteins; D003982:Dibekacin; C031986:arbekacin