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

Abstract

Positron emission tomography (PET) with [18Fjfleroxacin was used to study the pharmacokinetics of fleroxacin, a new broad-spectrum fluoroquinolone, in 12 healthy volunteers (9 men and 3 women). The subjects were infused with a standard therapeutic dose of fleroxacin (400 mg) supplemented with -20 mCi of[18F]fleroxacin. Serial PET images were made and blood samples were collected for 8 h, starting at the initiation of the infusion. The subjects were then treated with unlabeled drug for 3 days (400 mg/day). On the fifth day, infusion of radiolabeled drug, PET imaging, and blood collection were repeated. In most organs, there was rapid accumulation of radiolabeled drug, with stable levels achieved within 1 h after completion of the infusion.Especially high peak concentrations (in micrograms per gram) were achieved in the kidney (>34), liver (>25), lung (>20), myocardium (>19), and spleen (>18). Peak concentrations of drug more than two times the MIC for 90% of Enterobacteriaceae strains tested (>10-fold for most organisms) were achieved in all tissues except the brain and remained above this level for more than 6 to 8 h. The plateau concentrations in tissues (2 to 8 h, in micrograms per gram ± standard error of the mean) of drug were as follows: brain, 0.

Plasma vs heart tissue concentration in humans – literature data analysis of drugs distribution

“…The tissue pharmacokinetics of fleroxacin and trovafloxacin were studied in healthy subjects using positron emission tomography. Both quinolones exhibited a similar pattern of distribution with significant accumulation in all peripheral organs, also in the heart [94,95].…”

Issues in Pharmacokinetics and Pharmacodynamics of Anti-Infective Agents: Distribution in Tissue

“…The primary focus of SPECT was not the field of anti-infective drug evaluation but cancer research, and it is also used for staging, for diagnostic purposes (such as fever of unknown origin or otitis externa), and for local blood flow measurements (26,182). In vivo SPECT studies enabled quantitative measurements of the tissue PK of 57 Co-or 111 In-labeled bleomycin and 195m Pt-cisplatin in humans (61,77) and indicated that there is marked variability in drug delivery to given tissues. In the field of antibiotic evaluation, SPECT was used to evaluate the penetration of 99m Tc-labeled ciprofloxacin into inflammatory lesions (156).…”

“…As a conceptual extension of autoradiography (7,145,173), several novel imaging methods that lend themselves to the study of drug distribution in humans were developed (26,53,55,56,57,61,64,74,77,83,88,128,147,150,156,158,182,187). These comprised radiopharmaceutical techniques, such as two-dimensional planar gamma scintigraphy (PGS) (88,174), and three-dimensional techniques, such as single photon emission computed tomography (SPECT) (26,61,77,182), positron emission tomography (PET) (56,57,128,188) (Fig. 1), and magnetic resonance spectroscopy (MRS) (83,129,187), which does not require radioactive labeling.…”

“…1) and that target site drug levels may substantially differ from corresponding plasma drug levels (15,16,22,55,57,63,65,78,80,81,83,108,109,116,188). Suboptimal target site concentrations may have important clinical implications, as they may explain therapeutic failures (22,80,129), in particular, for bacteria for which in vitro MICs are high (22,80); in addition, it is conceivable that subinhibitory concentrations in tissues may also trigger bacterial resistance (76,87,117,120).…”

Protective Effect of Fleroxacin against the Nephrotoxicity of Isepamicin in Rats

“…14,17,18) Fleroxacin reaches peak kidney concentrations within 0.5-1 h. In fact, high concentrations of fleroxacin have been measured in the kidney of rabbits 19) and in the human kidneys. 20) Moreover, the accumulation of fleroxacin was higher in the kidneys of patients with symptomatic complicated urinary tract infections. 21) To our knowledge, there are no data on the effects of fleroxacin (orally) on the nephrotoxicity of administered isepamicin.…”