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

Araújo, Bibiana Verlindo de; Silva, Cristófer Farias da; Haas, Sandra Elisa; Costa, Teresa Dalla

doi:10.1016/j.ijantimicag.2008.08.020

Cited by 18 publications

(13 citation statements)

References 27 publications

(35 reference statements)

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“…The infection protocol for Wistar rats employed in this study was previously described by Araujo et al (4). Briefly, nonimmunocompromised animals were infected with C. albicans (ATCC 188041) 2 days prior to the pharmacokinetic experiments by i.v.…”

Section: Methodsmentioning

confidence: 99%

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Comparison of Fluconazole Renal Penetration Levels in Healthy and Candida albicans-Infected Wistar Rats

Azeredo

Araújo

Haas

et al. 2012

Antimicrob Agents Chemother

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The aims of this study were to evaluate free levels of fluconazole (FCZ) in the kidneys of healthy and Candida albicansinfected 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. albicansinfected 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.

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Section: Methodsmentioning

confidence: 99%

“…An evaluation of voriconazole renal penetration using microdialysis conducted by our research group using healthy Wistar rats in comparison with animals infected by Candida albicans and Candida krusei showed that systemic candidiasis did not affect renal penetration by this azole (4).…”

mentioning

confidence: 93%

Comparison of Fluconazole Renal Penetration Levels in Healthy and Candida albicans-Infected Wistar Rats

Azeredo

Araújo

Haas

et al. 2012

Antimicrob Agents Chemother

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“…No difference in RRs in vivo between healthy and infected animals was observed (P Ͼ 0.05). In general, the recoveries determined in vivo are lower than those determined in vitro due to biological characteristics of the tissues where the probes are inserted, such as tortuosity, interstitial fluid volume, drug uptake into cells, the active transport across membranes, the extent of tissue vascularization, and blood flow through the tissue, which can limit the diffusion of the drug through the probes (22). Our group observed an in vivo RR of VRC in renal tissue of 25.1% Ϯ 2.8% in the same flow (2 l/min) using a CMA 20 (22), and this slight difference can be explained by the type of probe and tissue investigated.…”

Section: Microdialysismentioning

confidence: 97%

Influence of Experimental Cryptococcal Meningitis in Wistar Rats on Voriconazole Brain Penetration Assessed by Microdialysis

Alves

Staudt

Silva

et al. 2017

Antimicrob Agents Chemother

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To make advances in the treatment of cryptococcal meningitis, it is crucial to know a given drug's free fraction that reaches the biophase. In the present study, we applied microdialysis (D) as a tool to determine the free levels reached by voriconazole (VRC) in the brains of healthy and Cryptococcus neoformans-infected rats. The infection was induced by the intravenous (i.v.) administration of 1 ϫ 10 5 CFU of yeast. The dose administered was 5 mg/kg (of body weight) of VRC, given i.v. Plasma and microdialysate samples were analyzed by liquid chromatographytandem mass spectrometry (LC-MS/MS) and LC-UV methods. The free brain/free plasma ratio (fT) and population pharmacokinetic (popPK) analyses were performed to evaluate the impact of infection on PK parameters of the drug. The brain penetration ratio showed an increase on brain exposure in infected animals (fT healthy ϭ 0.85 versus fT infected ϭ 1.86). The structural PK model with two compartments and Michaelis-Menten (MM) elimination describes the VRC concentration-time profile in plasma and tissue simultaneously. The covariate infection was included in volume of distribution in the peripheral compartment in healthy animals (V 2 ) and maximum rate of metabolism (V M ). The levels reached in infected tissues were higher than the values described for MIC of VRC for Cryptococccus neoformans (0.03 to 0.5 g ml Ϫ1 ), indicating its great potential to treat meningitis associated with C. neoformans.

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“…A limited number of studies that evaluated unbound tissue concentrations in animal infection models are available. For example, two separate studies sought to compare unbound plasma and tissue concentrations of voriconazole and fluconazole in healthy and Candida species-infected rats (128,129). In both cases, unbound plasma levels could serve as a good surrogate for unbound drug levels in the kidneys.…”

Section: In Vivo Studiesmentioning

confidence: 99%

Importance of Relating Efficacy Measures to Unbound Drug Concentrations for Anti-Infective Agents

2013

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SUMMARY For the optimization of dosing regimens of anti-infective agents, it is imperative to have a good understanding of pharmacokinetics (PK) and pharmacodynamics (PD). Whenever possible, drug efficacy needs to be related to unbound concentrations at the site of action. For anti-infective drugs, the infection site is typically located outside plasma, and a drug must diffuse through capillary membranes to reach its target. Disease- and drug-related factors can contribute to differential tissue distribution. As a result, the assumption that the plasma concentration of drugs represents a suitable surrogate of tissue concentrations may lead to erroneous conclusions. Quantifying drug exposure in tissues represents an opportunity to relate the pharmacologically active concentrations to an observed pharmacodynamic parameter, such as the MIC. Selection of an appropriate specimen to sample and the advantages and limitations of the available sampling techniques require careful consideration. Ultimately, the goal will be to assess the appropriateness of a drug and dosing regimen for a specific pathogen and infection.

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

Cited by 18 publications

References 27 publications

Comparison of Fluconazole Renal Penetration Levels in Healthy and Candida albicans-Infected Wistar Rats

Comparison of Fluconazole Renal Penetration Levels in Healthy and Candida albicans-Infected Wistar Rats

Influence of Experimental Cryptococcal Meningitis in Wistar Rats on Voriconazole Brain Penetration Assessed by Microdialysis

Importance of Relating Efficacy Measures to Unbound Drug Concentrations for Anti-Infective Agents

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