Influence of the infusion rate on disposition of netilmicin in the isolated rat perfused kidney.
A study of the disposition of netilmicin in the isolated rat kidney was carried out in order to establish the influence of the infusion rate on the drug profile in this tissue. A dose of 800 microg administered as a bolus injection or at infusion times of 5, 7.5 and 10 min, respectively, was injected through the afferent cannula into the isolated kidney. Analysis of outflow curves was carried out using different kinetic approaches. Comparison of statistical moments and derived parameters pointed to changes in the distribution process with the infusion rate. In contrast, elimination remained constant, since the extraction coefficient and relative area under the curve values did not change with the infusion rate, although the MTT (mean transit time) and distribution volume decreased for the longest infusion times. The UDF (unit disposition function) profiles were not superimposed for the different infusion rates and combined with the results of the kinetic analysis revealed that the behaviour of netilmicin in the isolated kidney depends on infusion rate. The apparent partition coefficients in renal cortex and medulla showed higher values for the slower perfusion rates. Yet, a progressive decrease in the absolute amount of netilmicin was predicted in the tubular epithelium compartment whereas the residence time tended to increase. The latter phenomenon could account for the higher aminoglycoside nephrotoxicity reported when these drugs are administered over longer infusion times.
Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Salamanca, Avda. Campo Charro s/n, 37007, Salamanca, Spain.
Aránzazu
A
Zarzuelo
José M
JM
Lanao
Francisco G
FG
López
Amparo
A
Sánchez-Navarro
D000818:Animals; D019540:Area Under Curve; D066298:In Vitro Techniques; D007261:Infusions, Intra-Arterial / Q000379:methods; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008954:Models, Biological; D009428:Netilmicin / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D010477:Perfusion / Q000379:methods; D051381:Rats; D017208:Rats, Wistar
D009428:Netilmicin