PLASMA PHARMACOKINETICS AND METABOLISM OF THE BENZODIAZEPINE ANTAGONIST [C-11] RO 15-1788 (FLUMAZENIL) IN BABOON AND HUMAN DURING POSITRON EMISSION TOMOGRAPHY STUDIES

Flumazenil is a specific antagonist of the central benzodiazepine receptor (CBZR). Labelled with C-11, this compound is the reference radioligand for positron emission tomography (PET) study of the CBZR in humans and primates. The time-course of [C-11]-flumazenil radioactivity and its main acid metabolite [C-11] Ro 15-3890 were reconstructed from the time-course of total radioactivity in plasma after administration with high or low SRA in primates and humans, applying an extraction procedure validated by TLC. The measured pharmacokinetics of [C-11]-flumazenil (T1/2-beta = 45.1 +/- 12.3 min, T1/2-alpha = 1.5 +/- 1.5 min; K = 0.14 +/- 0.14 min-1; Vd area = 44.0 +/- 17.0 l; Clp = 40.0 +/- 8.5 l/h) exhibited a very rapid distribution phase followed by fast elimination, with a large volume of distribution; these results were confirmed by HPLC determinations and agree with previously published data on unlabelled flumazenil. Pharmacokinetics of [C-11] Ro 15-3890 acid metabolite show that high drug concentrations in the blood are promptly achieved (kf = 0.13 +/- 0.004 min-1), with a very rapid elimination half-life (T1/2m = 4.47 +/- 1.31 min) comparable to that of [C-11]-flumazenil. The percentage metabolization of parent compound to the acid [C-11] Ro 15-3890 was constant from the 15th minute and was significantly higher in man compared to the monkey. This percentage was increased by prior eating. The other putative metabolites, i.e. labelled [C-11] Ro 15-4965 and unlabelled Ro 15-5528, were never observed at detectable concentrations with TLC and HPLC in rabbit, baboon and human blood samples. This pharmacokinetic study of plasma flumazenil may be useful to implement a dynamic method of CBZR quantification using PET and for analysis of pharmacokinetics in brain tissue.