1: J Pharm Sci. 2005 Apr;94(4):770-80. 

Fluconazole distribution in rat dermis following intravenous and topical
application: A microdialysis study.

Mathy FX, Ntivunwa D, Verbeeck RK, Preat V.

Unite de Pharmacie Galenique, Universite catholique de Louvain, Av. E. Mounier
73, UCL 73.20, 1200 Brussels Belgium.

The objective of this study was to investigate the skin distribution of
fluconazole, a water-soluble antifungal agent, following intravenous (i.v.) and
topical administration in the awake freely moving rat. Following i.v. bolus
injection of fluconazole (10 mg/kg), a dual-site microdialysis sampling was
performed in jugular vein and dermis in five rats. In addition, cutaneous
absorption was studied by dermal microdialysis sampling following topical
application of Diflucan(R) Gel 0.5% to 12 rats. Fluconazole microdialysate
concentrations were measured by on-line HPLC. To calibrate in vivo the probes, a
fluorinated analog (UK-54737) of fluconazole was used as retrodialysis marker
after demonstrating that recoveries were no different. Following i.v. bolus
injection, fluconazole rapidly penetrates into the dermis. Cutaneous
microdialysis sampling provided dermal concentrations of fluconazole, which were
very similar to the unbound plasma concentrations determined by vascular
microdialysis. The distribution equilibrium was rapidly achieved with a
dermis-to-plasma partition coefficient of 1.02 +/- 0.04 (n = 5). Following
topical application of 0.5 g of Diflucan Gel(R) containing 0.5% of fluconazole,
active unbound concentrations in dermis were measured by cutaneous microdialysis
for 11 h after application. The area under the curve (AUC) of fluconazole in
dermal dialysate was relatively constant to an implantation depth of
approximately 350 mum. Below this depth, the AUC progressively decreased with
increasing implantation depth of the probe. Finally, this study shows that
cutaneous microdialysis is an effective and minimally invasive tool to evaluate
the dermal pharmacokinetics of fluconazole following intravenous or topical
administration. (c) 2005 Wiley-Liss, Inc. and the American Pharmacists
Association J Pharm Sci 94:770-780, 2005.

PMID: 15729707 [PubMed - in process]