Combined PET and microdialysis for in vivo assessment of intracellular drug pharmacokinetics in humans.
Because many drugs possess an intracellular site of action, the knowledge of intracellular concentration-time profiles is desirable. In the present study, PET, which measures total (i.e., intracellular, extracellular, and intravascular) concentrations of radiolabeled drugs in tissue, and microdialysis, which determines unbound drug concentrations in the extracellular space fluid of tissue, were combined to describe the intracellular pharmacokinetics of a model compound--that is, the (18)F-labeled antibiotic (18)F-ciprofloxacin--in vivo in humans.


METHODS
Ten healthy male volunteers received a mixture of 687 +/- 50 MBq of (18)F-ciprofloxacin and 200 mg of unlabeled ciprofloxacin as an intravenous bolus infusion over 10 min. The pharmacokinetics of ciprofloxacin in skeletal muscle tissue were assessed by means of combined PET and in vivo microdialysis for 5 h after drug administration. A 3-compartment pharmacokinetic model was fitted to the tissue concentration-time profiles of ciprofloxacin measured by PET to estimate the rate constants of ciprofloxacin uptake and transport.


RESULTS
In muscle tissue, mean total and extracellular peak concentration (C(max)) values of ciprofloxacin of 1.8 +/- 0.4 microg/mL and 0.7 +/- 0.2 microg/mL were attained at 95 +/- 34 min and 48 +/- 20 min after drug administration, respectively. The extracellular-to-intracellular exchange appeared to be very fast, with an estimated rate constant k(3) of 1.69 +/- 0.25 min(-1). An intracellular-to-extracellular concentration ratio (C(intra)/C(extra)) of 3.2 +/- 0.8 was reached at 110 min after injection and followed by sustained intracellular retention of the antibiotic for the remainder of the experiment. The predicted extracellular concentration-time profiles from the compartmental modeling were in good agreement with the measured microdialysis data.


CONCLUSIONS
The results obtained in the present study were in accordance with previous in vitro data describing cellular ciprofloxacin uptake and retention. The presently used PET/microdialysis combination might be useful during research and development of new drugs, for which knowledge of intracellular concentrations is of interest.
Langer
Oliver
O
Department of Clinical Pharmacology, Division of Clinical Pharmacokinetics, Medical University of Vienna, Vienna, Austria. oliver.langer@meduniwien.ac.at
Karch
Rudolf
R
Müller
Ulrich
U
Dobrozemsky
Georg
G
Abrahim
Aiman
A
Zeitlinger
Markus
M
Lackner
Edith
E
Joukhadar
Christian
C
Dudczak
Robert
R
Kletter
Kurt
K
Müller
Markus
M
Brunner
Martin
M
D000328:Adult; D000465:Algorithms; D002939:Ciprofloxacin / Q000493:pharmacokinetics* / Q000627:therapeutic use; D003198:Computer Simulation; D005462:Fluorine Radioisotopes / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D007090:Image Interpretation, Computer-Assisted / Q000379:methods*; D007424:Intracellular Fluid / Q000378:metabolism; D007700:Kinetics; D008297:Male; D008657:Metabolic Clearance Rate; D017551:Microdialysis / Q000379:methods*; D008954:Models, Biological; D018482:Muscle, Skeletal / Q000000981:diagnostic imaging / Q000378:metabolism*; D009928:Organ Specificity; D049268:Positron-Emission Tomography / Q000379:methods*; D014018:Tissue Distribution
D005462:Fluorine Radioisotopes; D002939:Ciprofloxacin