JAC Advance Access published online on January 11, 2008
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkm512
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Influences of dosage regimen and co-administration of low-molecular weight proteins and basic peptides on renal accumulation of arbekacin in mice
Department of Pharmaceutics and Therapeutics, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan
Received 2 July 2007; returned 11 October 2007; revised 31 August 2007; accepted 4 December 2007
* Corresponding author. Tel: +81-82-257-5315; Fax: +81-82-257-5319; E-mail: takanom{at}hiroshima-u.ac.jp
Objectives: 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.
Key Words: aminoglycoside , renal uptake kinetics , once-daily dosing , megalin , nephrotoxicity