Pharmacokinetics of 18F-labeled fleroxacin in rabbits with Escherichia coli infections, studied with positron emission tomography

Abstract

'8F-labeled fleroxacin was used to measure the pharmacokinetics of fieroxacin in healthy and infected animals by positron emission tomography (PET) and tissue radioactivity measurements. In all experiments, a pharmacological dose of unlabeled drug (10 mJkg) was coinjected with the tracer. The pharmacokinetics of [18FJfleroxacin was measured in groups of healthy mice (n = six per group) at 10, 30, 60, and 120 min after inijection and in groups of rats with Escherchia coli thigh infections (n = six per group) at 60 and 120 min after injection by radioactivity measurements in excised tissues. In healthy rabbits (n = 4) and in rabbits with E. coli thigh infections (n = 4), tissue concentrations of drug were determined by serial PET imaging over 2 h; after the final image was acquired, animals were sacrificed and concentrations measured by PET were compared with the results of tissue radioactivity measureinents. In all three species, there was rapid equilibration of[18F]fleroxacin to significant concentratiobs in most peripheral organs; low concentrations of drug were detected in the brain. Accumulations of radiolabeled drug in infected and healthy thigh muscles were similar. Peak concentrations of drug of more than three times the MIC for 90% of members of the family Enterobacteriaceae (>100-fold for most organisms) were achieved in all tissues except brain and remained above this level for more than 2 h. Especially high peak concentrations were achieved in the kidney (>75 ,ug/g), liver (>50 ,ug/g), blood (>25 ,g/g), and bone and lung (>10 Fg/g). Since the MICs for 90% of all Enterobacteriaceae are <2 ,ug/ml, fleroxacin should be particularly useful in treating gram-negative infections affecting these tissues. In contrast, the low concentration of drug delivered to the brain should limit the toxicity of the drug for the central nervous systens.

Tissue Penetration of Antifungal Agents

“…7). However, in rabbit spleens, concentrations are similar to those in the blood (71,213) but slightly less than those in the plasma (185). Human data are limited for itraconazole, but splenic concentrations in two patients were 2-to 3-fold higher than the plasma concentrations (73,186).…”

“…Fluconazole penetrates into the spleen in both humans and rabbits, although to different extents (71,185,213). Higher concen-trations of 18 F-fluconazole are seen in human spleens than in any other organ, with a tissue/blood concentration ratio of approximately 6 (Fig.…”

Pharmacokinetics of [18F]fleroxacin in healthy human subjects studied by using positron emission tomography

“…In summary, the promise of PET scanning for delineating the tissue distribution of fleroxacin, an important new fluoroquinolone, which was suggested in earlier animal studies (15,34) …”

“…Thus, PET imaging permits the precise noninvasive measurement of the concentration of drug over time in various tissues, including sites of infection. The limitations of this approach have to do with the spatial resolution of PET (tissue volumes of >1.0 cm3) and the short physical half-life of 18F, which limits the time frame of pharmacokinetic measurements to 8 to 10 h. In the case of fleroxacin, these constraints have not prevented the acquisition of detailed tissue pharmacokinetic data, previously for animals (15,34) and now for humans. However, the fact that the sampling time was relatively short compared with the terminal half-life of fleroxacin limits the robustness of the method.…”

“…Previous studies in animals have validated this technique and demonstrated that PET imaging will permit the precise, noninvasive measurement of the concentrations of fleroxacin in various tissues over time (15,34). We report here the results of tissue pharmacokinetic studies utilizing this technique in healthy human subjects.…”