Pharmacokinetics of ¹⁸F-labeled fluconazole in rabbits with candidal infections studied with positron emission tomography

[4-¹⁸F]Fluconazole was used to measure the pharmacokinetics of fluconazole in normal and infected animals. The biodistribution of fluconazole was determined after administration of the ¹⁸F-tracer with/without a pharmacological dose of unlabeled drug by radioactivity measurements on excised tissues. In normal rabbits and rabbits with candidal infection of the thigh, tissue concentrations of drug were determined by serial positron emission tomographic imaging. In rats, coinjection of tracer quantities of [4-¹⁸F]fluconazole with a pharmacological dose of unlabeled drug resulted in a relatively uniform distribution of radioactivity in most organs, whereas, when the ¹⁸F-tracer was injected alone, spleen, muscle and heart accumulation was decreased and liver accumulation was increased. In rabbits, this effect was less pronounced. Early accumulation of [4-¹⁸F]fluconazole was greater in infected muscle. The areas under the 2-hr uptake curves were 4.30 and 6.05 μg·hr·ml^-1 for normal and infected tissue. A mathematical model was used to summarize the kinetics of fluconazole in normal and infected muscle. The model hypothesizes that fluconazole is compartmentalized in blood and tissue, with rate constants describing the transition between compartments. Direct measurement of the partition coefficient of fluconazole in muscle and predictions of the kinetic model were in close agreement, suggesting that fluconazole enters muscle via a passive transport mechanism. Transport rates of fluconazole, into (K(in)) and out of tissue (k(out)), were increased in infected compared with normal muscle, possibly due to increased capillary permeability (K(in): 0.064 ± 0.001 vs. 0.0270 ± 0.0002, k(out): 0.063 ± 0.002 vs. 0.035 ± 0.001).