A non specific permeabilization of the BBB, probably related to the toxicity of the carrier, may account for the CNS penetration of dalargin associated with PBCA NP and polysorbate 80.
1 The objective of this study was to investigate the contribution of norfloxacin blood-brain barrier (BBB) transport to its delayed electroencephalogram (EEG) effect in rats. 2 Norfloxacin was injected as a bolus dose of 150 mg kg À1 . Blood samples were collected for total norfloxacin plasma concentration measurements. The corresponding unbound levels were determined in brain extracellular fluid (ECF) using microdialysis. Quantitative EEG recording was conducted during 9 h post-dose. 3 Brain ECF norfloxacin concentrations were much lower than plasma levels (AUC ratio ¼ 9.772.8%) but peaked very early, and concentration versus time profiles were parallel in both biological fluids. The best pharmacokinetic (PK) modelling was obtained by considering that ECF concentrations were part of the central compartment, with a proportionality factor. The peak of EEG effect was delayed and the effect versus plasma concentration curves exhibited a dramatic hysteresis. A PK-pharmacodynamic (PD) effect compartment model with a spline function to describe the relationship between effect and concentration at the effect site successfully described the data. 4 Comparisons of PK-PD parameters estimated from plasma and ECF concentrations show that most of the delayed norfloxacin EEG effect is not due to BBB transport, but also that PD parameters derived from plasma data must be carefully interpreted when drug distribution at the effect site is restricted, as may often be the case for centrally acting drugs.
The purpose of this study was to compare the nephrotoxicity of gentamicin and vancomycin alone and in combination. Thirty-two male Sprague-Dawley rats were randomized into 4 groups of 8 animals. Each group received 200mg/kg gentamicin (G) i.m., or 300 mg/kg vancomycin (V) i.v., or an association of 200 mg/kg gentamicin + 300 mg/kg vancomycin (i.m. and i.v., respectively), or 0.9% NaCl solution i.m. and i.v. (controls). To determine AAP, GGT, and NAG enzyme excretions, urine samples were taken over 24-h periods before and after the start of the experiment. A single renal cortical sample was obtained at necropsy for quantitation of antibiotic levels. No significant modifications of urinary excretions of creatinine and enzymuria were noted during the 24-h period before each drug administration or in controls. AAP, GGT, and NAG excretions were significantly increased after G and G + V injections (p < 0.001), whereas only AAP and GGT were statistically higher in rats receiving V (p < 0.05). NAG elimination (mean +/- SD) was higher in G + V (16.0 +/- 0.2 IU/mmol creatinine/24 h; p < 0.001) than g (8.8 +/- 0.6) or V (1.7 +/- 0.2). Surprisingly, mean vancomycin cortical levels decreased in the combination (827 +/- 131 vs. 1964 +/- 23 micrograms/g for V alone; p < 0.001), whereas gentamicin concentration was unchanged (826 +/- 66 vs. 839 +/- 28 micrograms/g for G alone). Determination of enzymuria allowed the nephrotoxicity of the antibiotics to be graded in the following order: vancomycin + gentamicin > gentamicin > vancomycin.
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