Dermal pharmacokinetics of pyrazinamide determined by microdialysis sampling in rats

Publication: Int J Antimicrob Agents
Division: Simulations Plus


Studies have demonstrated pyrazinamide’s efficacy against stages of the parasite which causes cutaneous leishmaniasis. Although pyrazinamide is widely distributed to most fluids and tissues, the drug distribution that reaches the skin is unknown. The aim of this study was to investigate pyrazinamide pharmacokinetics in rat dermal tissue by dermal microdialysis. Skin pharmacokinetics were assessed by implanting a linear microdialysis probe in the dermis of ten rats. Additionally, blood samples were collected for assessing plasma pharmacokinetics. Unbound microdialysate samples (N = 280) and plasma (N = 120) concentrations after single intravenous doses of 25 or 50 mg/kg pyrazinamide were quantified by a validated HPLC method. Probe calibration was performed by retrodialysis. A non-compartmental analysis and non-linear mixed-effect modeling were performed using WinNonlin and NONMEM version 7.3. Pyrazinamide rapidly permeated into the dermis and reached high levels with an average maximum concentration (Cmax) of 22.4 ± 7.1 and 48.6 ± 17.3 µg/ml for the doses studied. Levels of pyrazinamide showed a significant distribution to the skin (fAUCdermal/fAUCplasma = 0.82 ± 0.3 and 0.84 ± 0.2) for 25 and 50 mg/kg, respectively. Active unbound concentrations in dermal tissue reached lower levels than free plasma concentrations, indicating that the free pyrazinamide levels in plasma were in equilibrium with the tissue levels. These results showed equivalent unbound drug tissue concentrations and corresponding unbound plasma levels. In conclusion, this study shows that PZA distributes rapidly into dermal interstitial fluid space in rats and therefore may be a potential agent in the treatment of cutaneous leishmaniasis.

By Nivea M.F. Voelkner, Alexander Voelkner, Juliana Costa, Sherwin K.B. Sy, Juliane Hermes, Johanna Weitzel, Sebastian Morales & Hartmut Derendorf