Mathy François-Xavier, Ntivunwa Denis, Verbeeck Roger K, Préat Véronique
Unité de Pharmacie Galénique, Université catholique de Louvain, Av. E. Mounier 73, UCL 73.20, 1200 Brussels, Belgium.
J Pharm Sci. 2005 Apr;94(4):770-80. doi: 10.1002/jps.20290.
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 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 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 microm. 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.
本研究的目的是在清醒自由活动的大鼠中，研究水溶性抗真菌药氟康唑静脉注射和局部给药后的皮肤分布情况。静脉推注氟康唑（10mg/kg）后，对5只大鼠的颈静脉和真皮进行双位点微透析采样。此外，对12只大鼠局部应用0.5%氟康唑凝胶后，通过皮肤微透析采样研究皮肤吸收情况。通过在线高效液相色谱法测定氟康唑微透析液浓度。为了在体内校准探针，在证明回收率无差异后，使用氟康唑的氟化类似物（UK-54737）作为反透析标记物。静脉推注后，氟康唑迅速渗透到真皮中。皮肤微透析采样提供了氟康唑的真皮浓度，其与通过血管微透析测定的未结合血浆浓度非常相似。分布平衡迅速达到，真皮与血浆的分配系数为1.02±0.04（n=5）。局部应用含0.5%氟康唑的0.5g氟康唑凝胶后，应用后11小时通过皮肤微透析测量真皮中的活性未结合浓度。氟康唑在皮肤透析液中的曲线下面积（AUC）在植入深度约为350微米时相对恒定。在此深度以下，AUC随着探针植入深度的增加而逐渐降低。最后，本研究表明，皮肤微透析是评估氟康唑静脉或局部给药后皮肤药代动力学的一种有效且微创的工具。
