The ability of fluconazole to penetrate into ventilated, healthy and inflamed lung tissue in a model of severe sepsis in rats

• Published in: Pharmacology Vol. 87; no. 3-4; p. 130
• Main Authors: Mauric, Oliver, Thallinger, Christiane, Kugler, Sylvia A, Joukhadar, Samir M, Kovar, Florian M, Konz, Karl H, Graninger, Wolfgang, Joukhadar, Christian
• Format: Journal Article
• Language: English
• Published: Switzerland 01-01-2011
• Subjects: Animals; Antifungal Agents - administration & dosage; Antifungal Agents - blood; Antifungal Agents - pharmacokinetics; Blood Proteins - metabolism; Disease Models, Animal; Extracellular Space - metabolism; Fluconazole - administration & dosage; Fluconazole - blood; Fluconazole - pharmacokinetics; Injections, Intravenous; Lipopolysaccharides - toxicity; Lung - metabolism; Male; Microdialysis; Muscle, Skeletal - metabolism; Protein Binding; Rats; Rats, Wistar; Sepsis - drug therapy; Sepsis - metabolism; Severity of Illness Index; Systemic Inflammatory Response Syndrome - metabolism
• ISSN: 1423-0313
• DOI: 10.1159/000323738

We measured the extracellular concentrations of fluconazole in lung tissue of septic and healthy rats.
A single intravenous dose of 6 mg/kg total body weight of fluconazole was administered intravenously to rats following insertion of microdialysis probes into lung tissue. Another probe was inserted into skeletal muscle and served as control.
The mean peak concentration (C(max)), time to C(max), area under the concentration-versus-time curve from 0 to 6 h (fAUC(0-6)) and area under the concentration-versus-time curve from 0 to ∞ of unbound fluconazole for healthy lung were 11.0 ± 2.3 mg/l, 1.9 ± 1.5 h, 47.4 ± 8.6 mg·h/l and 233.7 ± 121.1 mg·h/l, respectively. The corresponding values for inflamed lung were 11.8 ± 1.7 mg/l, 1.5 ± 0.0 h, 52.9 ± 6.2 mg·h/l and 212.6 ± 79.7 mg·h/l, respectively. The mean apparent terminal elimination half-lives of fluconazole ranged from 12.3 to 22.4 h between compartments. The ratios of the fAUC(0-6) for lung to the fAUC(0-6) for plasma were 1.38 ± 0.39 and 1.32 ± 0.04 for healthy and inflamed lung, respectively.
We provide evidence that free fluconazole levels in plasma, the extracellular space fluid of lung tissue and skeletal muscle are almost superimposable during inflammatory and normal conditions.