Free renal levels of voriconazole determined by microdialysis in healthy and Candida sp.-infected Wistar rats

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 (40 mg/kg or 60 mg/kg) was administered orally (n = 6 per group) and blood and microdialysate samples were collected at predetermined time points up to 18 h. The mean area under the total concentration–time curve (AUC0–∞) in healthy animals increased from 44.2 ± 7.3 μg/h/mL to 78.8 ± 4.0 μg/h/mL for plasma and from 15.1 ± 2.4 μg/h/mL to 27.9 ± 2.6 μg/h/mL for tissue after 40 mg/kg and 60 mg/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 AUC0–∞ 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.