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

Authors

  • Alan J. Fischman,

    Corresponding author
    1. Division of Nuclear Medicine of the Department of Radiology, Massachusetts General Hospital, and the Department of Radiology, Harvard Medical School, Boston MA, USA
    2. Center for Experimental Pharmacology and Therapeutics, Harvard-MIT, Division of Health Sciences and Technology, Cambridge MA, USA
    Search for more papers by this author
  • John W. Babich,

    1. Division of Nuclear Medicine of the Department of Radiology, Massachusetts General Hospital, and the Department of Radiology, Harvard Medical School, Boston MA, USA
    Search for more papers by this author
  • Nathaniel M. Alpert,

    1. Division of Nuclear Medicine of the Department of Radiology, Massachusetts General Hospital, and the Department of Radiology, Harvard Medical School, Boston MA, USA
    Search for more papers by this author
  • John Vincent,

    1. Central Research Division, Pfizer Inc., Groton CT, USA
    Search for more papers by this author
  • Robert A. Wilkinson,

    1. Division of Nuclear Medicine of the Department of Radiology, Massachusetts General Hospital, and the Department of Radiology, Harvard Medical School, Boston MA, USA
    Search for more papers by this author
  • Ronald J. Callahan,

    1. Division of Nuclear Medicine of the Department of Radiology, Massachusetts General Hospital, and the Department of Radiology, Harvard Medical School, Boston MA, USA
    Search for more papers by this author
  • John A. Correia,

    1. Division of Nuclear Medicine of the Department of Radiology, Massachusetts General Hospital, and the Department of Radiology, Harvard Medical School, Boston MA, USA
    Search for more papers by this author
  • Robert H. Rubin

    1. Division of Nuclear Medicine of the Department of Radiology, Massachusetts General Hospital, and the Department of Radiology, Harvard Medical School, Boston MA, USA
    2. Center for Experimental Pharmacology and Therapeutics, Harvard-MIT, Division of Health Sciences and Technology, Cambridge MA, USA
    Search for more papers by this author

Corresponding author and reprint requests: Alan J. Fischman, Division of Nuclear Medicine, Department of Radiology, Massachusetts General Hospital, 32 Fruit Street, Boston, MA 02114, USA Tel: (617) 726-8353 Fax: (617) 726-6165

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).

Method: Concentrations of [18]Ftrovafloxacin 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 [18]F 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.

Conclusions: PET with [18F] trovafloxacin is a useful technique for non-invasive measurements of tissue pharmacokinetics.

Ancillary