de Araujo Bibiana Verlindo, da Silva Cristófer Farias, Haas Sandra Elisa, Dalla Costa Teresa
Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Federal do Rio Grande do Sul, RS, Brazil.
Int J Antimicrob Agents. 2009 Feb;33(2):154-9. doi: 10.1016/j.ijantimicag.2008.08.020. Epub 2008 Nov 17.
The aims of this study were to evaluate free levels of voriconazole (VCZ) in the kidney of healthy and Candida albicans- or Candida krusei-infected Wistar rats using microdialysis and to establish the relationship between free renal and free plasma levels in both conditions. VCZ (40mg/kg or 60mg/kg) was administered orally (n=6 per group) and blood and microdialysate samples were collected at predetermined time points up to 18h. The mean area under the total concentration-time curve (AUC(0-infinity)) in healthy animals increased from 44.2+/-7.3microg/h/mL to 78.8+/-4.0microg/h/mL for plasma and from 15.1+/-2.4microg/h/mL to 27.9+/-2.6microg/h/mL for tissue after 40mg/kg and 60mg/kg VCZ dosing, respectively, showing non-linear pharmacokinetics described by a one-compartment model with Michaelis-Menten elimination. There were no statistical differences between the AUC(0-infinity) of plasma and tissue for either healthy or infected groups for the same dose. The antifungal tissue penetration was similar for both doses and all conditions investigated (0.34+/-0.06). VCZ protein binding was concentration-independent and was on average 66.0+/-4.0%, allowing the prediction of free renal levels using pharmacokinetic parameters obtained from total plasma fitting. The results showed that VCZ free renal and free plasma levels are similar in healthy rats and in rats with disseminated candidiasis caused by C. albicans or C. krusei. Therefore, plasma free levels can be used to optimise dosing regimens for this drug.
本研究的目的是使用微透析评估健康以及白色念珠菌或克鲁斯念珠菌感染的Wistar大鼠肾脏中伏立康唑（VCZ）的游离水平，并确定两种情况下肾脏游离水平与血浆游离水平之间的关系。口服给予VCZ（40mg/kg或60mg/kg）（每组n = 6），并在预定时间点直至18小时收集血液和微透析液样本。在给予40mg/kg和60mg/kg VCZ后，健康动物血浆中总浓度-时间曲线下的平均面积（AUC(0-∞)）分别从44.2±7.3μg/h/mL增加到78.8±4.0μg/h/mL，组织中从15.1±2.4μg/h/mL增加到27.9±2.6μg/h/mL，显示出由具有米氏消除的一室模型描述的非线性药代动力学。相同剂量下，健康组或感染组血浆和组织的AUC(0-∞)之间无统计学差异。两种剂量以及所有研究条件下的抗真菌组织穿透率相似（0.34±0.06）。VCZ蛋白结合与浓度无关，平均为66.0±4.0%，这使得可以使用从总血浆拟合获得的药代动力学参数预测肾脏游离水平。结果表明，健康大鼠以及由白色念珠菌或克鲁斯念珠菌引起播散性念珠菌病的大鼠中，VCZ的肾脏游离水平和血浆游离水平相似。因此，血浆游离水平可用于优化该药物的给药方案。
