Population pharmacokinetic analysis for simultaneous determination of B (max) and K (D) in vivo by positron emission tomography.
OBJECTIVE
Changes in GABA(A)-receptor density and affinity play an important role in many forms of epilepsy. A novel approach, using positron emission tomography (PET) and [C-11]flumazenil ([C-11]FMZ), was developed for simultaneous estimation of GABA(A)-receptor properties, characterized by B (max) and K (D).


METHODS
Following an injection of [C-11]FMZ (dose range: 1-2,000 mug) to 21 rats, concentration time curves of FMZ in brain (using PET) and blood (using HPLC-UV) were analyzed simultaneously using a population pharmacokinetic (PK) model, containing expressions to describe the time course of the plasma concentration (including distribution to the body), the brain distribution, and the specific binding within the brain.


RESULTS
Application of this method in control rats resulted in estimates of B (max) and K (D) (14.5 +/- 3.7 ng/ml and 4.68 +/- 1.5 ng/ml, respectively).


CONCLUSIONS
The proposed population PK model allowed for simultaneous estimation of B (max) and K (D) for a group of animals using single injection PET experiments per animal.
Liefaard
Lia C
LC
Division of Pharmacology, LACDR, Leiden University, P.O. Box 9502, 2300 RA, Leiden, The Netherlands.
Ploeger
Bart A
BA
Molthoff
Carla F M
CF
Boellaard
Ronald
R
Lammertsma
Adriaan A
AA
Danhof
Meindert
M
Voskuyl
Rob A
RA
D000818:Animals; D001921:Brain / Q000378:metabolism; D002250:Carbon Radioisotopes; D005442:Flumazenil / Q000032:analysis / Q000097:blood / Q000493:pharmacokinetics*; D058787:GABA-A Receptor Antagonists; D008297:Male; D049268:Positron-Emission Tomography / Q000379:methods*; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000378:metabolism*
D002250:Carbon Radioisotopes; D058787:GABA-A Receptor Antagonists; D011963:Receptors, GABA-A; D005442:Flumazenil