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


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 µl/min), voriconazole concentration (1.0 - 50.0 µg/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 °C). A flow-rate dependency was shown (optimum: 2.0 µl/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 µg/ml for in vivo catheter calibration solutions.


CONCLUSIONS
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.
Simmel
F
F
Department of Clinical Pharmacy, Institute of Pharmacy, Martin-Luther-University Halle-Wittenberg, Halle, Germany.
Kloft
C
C
D000935:Antifungal Agents / Q000032:analysis* / Q000737:chemistry; D004355:Drug Stability; D005240:Feasibility Studies; D006801:Humans; D017551:Microdialysis / Q000379:methods*; D011743:Pyrimidines / Q000032:analysis* / Q000737:chemistry; D013997:Time Factors; D014230:Triazoles / Q000032:analysis* / Q000737:chemistry; D065819:Voriconazole
D000935:Antifungal Agents; D011743:Pyrimidines; D014230:Triazoles; D065819:Voriconazole