Human subcutaneous tissue distribution of fluconazole: comparison of microdialysis and suction blister techniques

Abstract

Aims To investigate uptake of fluconazole into the interstitial fluid of human subcutaneous tissue using the microdialysis and suction blister techniques. Methods A sterile microdialysis probe (CMA/60) was inserted subcutaneously into the upper arm of five healthy volunteers following an overnight fast. Blisters were induced on the lower arm using gentle suction prior to ingestion of a single oral dose of fluconazole (200 mg). Microdialysate, blister fluid and blood were sampled over 8 h. Fluconazole concentrations were determined in each sample using a validated HPLC assay. In vivo recovery of fluconazole from the microdialysis probe was determined in each subject by perfusing the probe with fluconazole solution at the end of the 8 h sampling period. Individual in vivo recovery was used to calculate fluconazole concentrations in subcutaneous interstitial fluid. A physiologically based pharmacokinetic (PBPK) model was used to predict fluconazole concentrations in human subcutaneous interstitial fluid. Results There was a lag-time (approximately 0.5 h) between detection of fluconazole in microdialysate compared with plasma in each subject. The in vivo recovery of fluconazole from the microdialysis probe ranged from 57.0 to 67.2%. The subcutaneous interstitial fluid concentrations obtained by microdialysis were very similar to the unbound concentrations of fluconazole in plasma with maximum concentration of 4.29 ± 1.19 m g ml -1 in subcutaneous interstitial fluid and 3.58 ± 0.14 m g ml -1 in plasma. Subcutaneous interstitial fluid-to-plasma partition coefficient (K p ) of fluconazole was 1.16 ± 0.22 (95% CI 0.96, 1.35). By contrast, fluconazole concentrations in blister fluid were significantly lower (P < 0.05, paired t-test) than unbound plasma concentrations over the first 3 h and maximum concentrations in blister fluid had not been achieved at the end of the sampling period. There was good agreement between fluconazole concentrations derived from microdialysis sampling and those estimated using a blood flow-limited PBPK model. Conclusions Microdialysis and suction blister techniques did not yield comparable results. It appears that microdialysis is a more appropriate technique for studying the rate of uptake of fluconazole into subcutaneous tissue. PBPK model simulation suggested that the distribution of fluconazole into subcutaneous interstitial fluid is dependent on tissue blood flow.

Pharmacokinetic Modeling of Free Amoxicillin Concentrations in Rat Muscle Extracellular Fluids Determined by Microdialysis

“…The very rapid distribution of AMX in MIF is consistent with previous knowledge on amino-␤-lactam antibiotic pharmacokinetics, suggesting that this process is rate limited not by permeability characteristics but rather by blood supply to the tissue (16). In agreement with that, the previously published blood flow-limited hybrid semiphysiological model (17,18) was satisfactory for describing the observed MIF data. In particular, the presumably virtually instantaneous distribution of AMX in MIF was predicted by the model, indicating that maximum MIF AMX concentrations should be reached at about 4 min postdosing, corresponding approximately to the middle of the time of the first microdialysate fraction (Fig.…”

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

“…One study sought to compare the skin blister and microdialysis techniques to evaluate the subcutaneous penetration of fluconazole following single-dose, oral administration. Microdialysis concentrations measured in the subcutaneous tissue were similar to unbound concentrations in plasma, although a lag time of 0.5 h was observed (108). On the other hand, flucona- zole concentrations measured in blister fluid were significantly low and delayed compared to plasma concentrations.…”

Tissue Penetration of Antifungal Agents

“…Fluconazole concentrations within the dermis are similar to those in plasma (216,217), but concentrations in the stratum corneum are up to 40 times those in plasma (217,218) (Fig. 7).…”