OtherClinical Investigations

Combined PET and Microdialysis for In Vivo Assessment of Intracellular Drug Pharmacokinetics in Humans

Oliver Langer, Rudolf Karch, Ulrich Müller, Georg Dobrozemsky, Aiman Abrahim, Markus Zeitlinger, Edith Lackner, Christian Joukhadar, Robert Dudczak, Kurt Kletter, Markus Müller and Martin Brunner
Journal of Nuclear Medicine November 2005, 46 (11) 1835-1841;

Article Figures & Data

Figures

  • FIGURE 1.
    FIGURE 1.

    Diagram of 3-compartment, 4-rate-constant (4K) model to describe ciprofloxacin pharmacokinetics in human skeletal muscle. Cp(t) is the input function, C1(t) denotes the extracellular concentration, and C2(t) denotes the intracellular concentration of ciprofloxacin. K1, k2, k3, and k4 are first-order rate constants describing exchange of ciprofloxacin between plasma and extracellular space as well as between extracellular and intracellular space.

  • FIGURE 2.
    FIGURE 2.

    Individual (A−C) and mean ± SD (D) concentration−time profiles of ciprofloxacin in plasma (A), extracellular space of skeletal muscle tissue (B), and total skeletal muscle (C) measured by combined microdialysis and PET after intravenous administration of a mixture of 687 ± 50 MBq of 18F-ciprofloxacin and 200 mg of unlabeled ciprofloxacin to 10 healthy male volunteers (P1−P10 indicate individual subjects).

  • FIGURE 3.
    FIGURE 3.

    Blood and tissue concentration−time profiles of ciprofloxacin and fits obtained from 3-compartment, 4-rate-constant pharmacokinetic model from 2 representative subjects (A, subject 2; B, subject 8). Microdialysis data points (Cextra) were corrected for extracellular protein binding.

  • FIGURE 4.
    FIGURE 4.

    Representative reversed-phase HPLC chromatogram of postdose urine obtained from 1 healthy volunteer at the end of PET experiment. HPLC eluate was monitored in series for ultraviolet absorption (wavelength, 280 nm; A) and for radioactivity (B). Arrow indicates 2 unidentified radiolabeled metabolites.

Tables

  • TABLE 1

    Pharmacokinetic Parameters (Mean ± SD) of Ciprofloxacin in Blood and Skeletal Muscle Tissue After Intravenous Administration of a Mixture of 687 ± 50 MBq of 18F-Ciprofloxacin and 200 mg of Unlabeled Ciprofloxacin to 10 healthy Male Volunteers

    CompartmentCmax (μg/mL)tmax (min)t1/2 (min)AUC0-n (μg · min · mL−1)
    Plasma6.5 ± 0.910 ± 0208 ± 49290 ± 30
    Total tissue [CPET(t)]1.8 ± 0.495 ± 34528 ± 142434 ± 76
    Extracellular tissue [Cextra-unbound(t)]0.7 ± 0.248 ± 20233 ± 88132 ± 33
  • TABLE 2

    Parameter Estimates (Mean ± SD) of 3-Compartment, 4-Rate-Constant Pharmacokinetic Model Used for Description of Ciprofloxacin Pharmacokinetics in Human Skeletal Muscle Tissue

    ParameterValue
    K1 [mL · mL−1 · min−1]0.02 ± 0.01
    k2 [min−1]0.21 ± 0.07
    k3 [min−1]1.69 ± 0.25
    k4 [min−1]0.07 ± 0.01
    Vb0.04 ± 0.01
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