Pharmacokinetics of 18F-labeled trovafloxacin in normal and Escherichia coli-infected rats and rabbits studied with positron emission tomography

Abstract

Objective: To measure tissue pharmacokinetics of trovafloxacin (CP 99,219) in normal and infected animals by both direct tissue radioactivity measurements and positron emission tomography (PET). Methods: Concentrations of [18F]trovafloxacin were measured in normal and infected rats (n = 6/group), at 10, 30, 60, and 120 min after injection, by radioactivity measurements. In normal rabbits (n = 4) and rabbits with Escherichia coli thigh infection (n = 4), tissue concentrations of drug were measured over 2 h with PET. After acquiring the final images, the rabbits were killed and tissue concentrations measured with PET were compared to the results of direct tissue radioactivity measurements. Results: In both species, there was rapid distribution of [18F] trovafloxacin in most peripheral organs. Peak concentrations of more than five times the MIC90 of most Enterobacteriaceae and anaerobes (> 100-fold for most organisms) were achieved in all tissues and remained above this level for > 2 h. Particularly high peak concentrations were achieved in the kidney (> 75 μg/g), liver (> 100 μg/g), blood (> 40 μg/g), and lung (> 10 μg/g). Even though the concentration of trovafloxacin in infected muscle was reduced (p < 0.01), the peak concentration was still > 4 μg/g and tissue levels remained above 2 μg/g for more than 2 h. Due to the lower concentrations that were achieved in the brain (peak ~ 5 μg/g), it is expected that trovafloxacin will have limited central nervous system toxicity. Conclusion: PET with [18F]trovafloxacin is a useful technique for non-invasive measurements of tissue pharmacokinetics.