Evaluation of gatifloxacin penetration into skeletal muscle and lung by microdialysis in rats

bLevofloxacin is a broad-spectrum fluoroquinolone used in the treatment of both acute and chronic bacterial prostatitis. Currently, the treatment of bacterial prostatitis is still difficult, especially due to the poor distribution of many antimicrobials into the prostate, thus preventing the drug to reach effective interstitial concentrations at the infection site. Newer fluoroquinolones show a greater penetration into the prostate. In the present study, we compared the unbound levofloxacin prostate concentrations measured by microdialysis to those in plasma after a 7-mg/kg intravenous bolus dose to Wistar rats. Plasma and dialysate samples were analyzed using a validated high-pressure liquid chromatography-fluorescence method. Both noncompartmental analysis (NCA) and population-based compartmental modeling (NONMEM 6) were performed. Unbound prostate tissue concentrations represented 78% of unbound plasma levels over a period of 12 h by comparing the extent of exposure (unbound AUC 0 -ؕ ) of 6.4 and 4.8 h·g/ml in plasma and tissue, respectively. A three-compartment model with simultaneous passive diffusion and saturable distribution kinetics from the prostate to the central compartment gave the best results in terms of curve fitting, precision of parameter estimates, and model stability.

Section: Discussionsupporting

confidence: 62%

mentioning

confidence: 99%

Population Pharmacokinetic Modeling of the Unbound Levofloxacin Concentrations in Rat Plasma and Prostate Tissue Measured by Microdialysis

Hurtado

Weber

Derendorf

et al. 2014

“…Before the beginning of all experiments, a 1-h probe equilibration period with perfusion of Ringer's solution at a flow rate of 1.5 l/min was performed. The surgical procedure for probe insertion used in this study is well described, and no major lung trauma induced by the microdialysis catheter has been reported in the literature (10,11,42,43).…”

Section: Methodsmentioning

confidence: 99%

Population Pharmacokinetic Modeling as a Tool To Characterize the Decrease in Ciprofloxacin Free Interstitial Levels Caused by Pseudomonas aeruginosa Biofilm Lung Infection in Wistar Rats

Torres

Helfer

Bernardes

et al. 2017

Biofilm formation plays an important role in the persistence of pulmonary infections, for example, in cystic fibrosis patients. So far, little is known about the antimicrobial lung disposition in biofilm-associated pneumonia. This study aimed to evaluate, by microdialysis, ciprofloxacin (CIP) penetration into the lungs of healthy and Pseudomonas aeruginosa biofilm-infected rats and to develop a comprehensive model to describe the CIP disposition under both conditions. P. aeruginosa was immobilized into alginate beads and intratracheally inoculated 14 days before CIP administration (20 mg/kg of body weight). Plasma and microdialysate were sampled from different animal groups, and the observations were evaluated by noncompartmental analysis (NCA) and population pharmacokinetic (popPK) analysis. The final model that successfully described all data consisted of an arterial and a venous central compartment and two peripheral distribution compartments, and the disposition in the lung was modeled as a two-compartment model structure linked to the venous compartment. Plasma clearance was approximately 32% lower in infected animals, leading to a significantly higher level of plasma CIP exposure (area under the concentration-time curve from time zero to infinity, 27.3 Ϯ 12.1 g · h/ml and 13.3 Ϯ 3.5 g · h/ml in infected and healthy rats, respectively). Despite the plasma exposure, infected animals showed a four times lower tissue concentration/plasma concentration ratio (lung penetration factor ϭ 0.44 and 1.69 in infected and healthy rats, respectively), and lung clearance (CL lung ) was added to the model for these animals (CL lung ϭ 0.643 liters/h/kg) to explain the lower tissue concentrations. Our results indicate that P. aeruginosa biofilm infection reduces the CIP free interstitial lung concentrations and increases plasma exposure, suggesting that plasma concentrations alone are not a good surrogate of lung concentrations.

“…The recoveries at higher FCZ concentrations (50, 100, and 500 g/ml) were also investigated. The relative recovery of FCZ (n ϭ 3) was determined by dialysis and retrodialysis using a 1-g/ml solution described previously (3,23).…”

Section: Methodsmentioning

confidence: 99%

Comparison of Fluconazole Renal Penetration Levels in Healthy and Candida albicans-Infected Wistar Rats

Azeredo

Araújo

Haas

et al. 2012

The aims of this study were to evaluate free levels of fluconazole (FCZ) in the kidneys of healthy and Candida albicansinfected Wistar rats using microdialysis and to establish the relationship between free renal and total plasma levels under both conditions. Microdialysis recovery rates were determined in vitro by dialysis, and retrodialysis recovery rates were determined in vivo by retrodialysis. The recovery rate was around 50%, independent of the method, drug concentration, or condition (in vitro or in vivo) used. FCZ kidney penetration in healthy and infected rats was investigated after the administration of 10 mg/kg of body weight intravenously (i.v.) or 50 mg/kg orally (n ‫؍‬ 6/group) and blood and microdialysate sample harvesting at predetermined time points up to 24 and 18 h, respectively. There were no statistical differences between the area under the free concentration-time curve (AUC 0 -ؕ ) values in plasma and in tissue for either healthy or infected groups for the same dose regimen investigated. The antifungal tissue penetrations were similar for both doses and under all conditions investigated (ranging from 0.77 to 0.84). The unbound fraction of FCZ was concentration independent (86.0% ؎ 2.0%), allowing the prediction of free renal levels using pharmacokinetic parameters obtained from total plasma fitting. The results showed that free renal and free plasma levels are similar in healthy and systemically C. albicansinfected rats. Therefore, free plasma levels are a good surrogate to estimate free FCZ renal concentrations in systemic candidiasis and can be used to optimize dosing regimens for this drug.