Programa de Pós-Graduação em Ciências Farmacêuticas, Faculdade de Farmácia, Universidade Federal do Rio Grande do Sul, Rio Grande do Sul, Brazil.
Antimicrob Agents Chemother. 2012 Nov;56(11):5852-7. doi: 10.1128/AAC.01323-12. Epub 2012 Sep 4.
The aims of this study were to evaluate free levels of fluconazole (FCZ) in the kidneys of healthy and Candida albicans-infected Wistar rats using microdialysis and to establish the relationship between free renal and total plasma levels under both conditions. Microdialysis recovery rates were determined in vitro by dialysis, and retrodialysis recovery rates were determined in vivo by retrodialysis. The recovery rate was around 50%, independent of the method, drug concentration, or condition (in vitro or in vivo) used. FCZ kidney penetration in healthy and infected rats was investigated after the administration of 10 mg/kg of body weight intravenously (i.v.) or 50 mg/kg orally (n = 6/group) and blood and microdialysate sample harvesting at predetermined time points up to 24 and 18 h, respectively. There were no statistical differences between the area under the free concentration-time curve (AUC(0-∞)) values in plasma and in tissue for either healthy or infected groups for the same dose regimen investigated. The antifungal tissue penetrations were similar for both doses and under all conditions investigated (ranging from 0.77 to 0.84). The unbound fraction of FCZ was concentration independent (86.0% ± 2.0%), allowing the prediction of free renal levels using pharmacokinetic parameters obtained from total plasma fitting. The results showed that free renal and free plasma levels are similar in healthy and systemically C. albicans-infected rats. Therefore, free plasma levels are a good surrogate to estimate free FCZ renal concentrations in systemic candidiasis and can be used to optimize dosing regimens for this drug.
本研究旨在使用微透析评估健康和白色念珠菌感染的 Wistar 大鼠肾脏中的氟康唑（FCZ）游离水平，并建立两种情况下游离肾和总血浆水平之间的关系。通过透析在体外测定微透析回收率，通过逆行透析在体内测定逆行透析回收率。回收率约为 50%，与方法、药物浓度或使用的条件（体外或体内）无关。在给予 10 mg/kg 体重静脉内（i.v.）或 50 mg/kg 口服（n = 6/组）后，研究了健康和感染大鼠中 10 mg/kg 体重静脉内（i.v.）或 50 mg/kg 口服（n = 6/组）后 FCZ 对健康和感染大鼠的肾脏穿透性，并在预定时间点采集血液和微透析液样本，分别为 24 和 18 小时。对于相同的剂量方案，健康或感染组的游离浓度-时间曲线下面积（AUC(0-∞)）值在血浆和组织中均无统计学差异。对于两种剂量和所有研究条件（范围为 0.77 至 0.84），抗真菌组织穿透性相似。FCZ 的未结合分数与浓度无关（86.0%±2.0%），允许使用总血浆拟合获得的药代动力学参数预测游离肾水平。结果表明，健康和系统性白色念珠菌感染大鼠的游离肾和游离血浆水平相似。因此，游离血浆水平可作为估计系统性念珠菌病中游离 FCZ 肾浓度的良好替代物，并可用于优化该药物的给药方案。
