Microdialysis feasibility investigations with the non-hydrophilic antifungal voriconazole for potential applications in nonclinical and clinical settings.

摘要

OBJECTIVE: This study aimed at investigating the feasibility and validity of the microdialysis technique for the non-hydrophilic antifungal voriconazole, in settings for established concentric and new linear catheters. Optimal conditions for application of microdialysis in in vivo studies including steady-state conditions were to be elaborated. MATERIALS AND METHODS: For in vitro microdialysis investigations, a robust and easy-to-handle system was developed permitting standardized physiological-like conditions. Various experiments on the influence of flow-rate (0.4 - 10.0 microl/min), voriconazole concentration (1.0 - 50.0 microg/ml) on relative recovery were performed. Additionally, the mass transfer coefficient r of voriconazole was estimated (WinNonlin). RESULTS: In vitro microdialysis experiments suggested sufficient voriconazole concentrations in the dialysate for (non-)clinical investigations. The stability of voriconazole was confirmed over 10 h (37 degrees C). A flow-rate dependency was shown (optimum: 2.0 microl/min) and r was estimated to be 0.09 mm/min and 0.11 mm/min for concentric and linear catheters, respectively. Relative recovery in delivery/recovery experiments was independent of the voriconazole concentration ranging from 96.0% to 97.8%/93.8% to 100.2% (CV 1.7%/ 0.5%) indicating unhampered passage of voriconazole through the catheter. Investigations mimicking steady-state suggested voriconazole concentration of 100 - 200 microg/ml for in vivo catheter calibration solutions. CONCLUSION: The results demonstrate the feasibility and validity of the microdialysis technique in clinically-mimicked settings despite the higher lipophilicity of voriconazole and support the application of the technique in vivo.