BENZODIAZEPINE RECEPTOR EQUILIBRIUM-CONSTANTS FOR FLUMAZENIL AND MIDAZOLAM DETERMINED IN HUMANS WITH THE SINGLE-PHOTON EMISSION COMPUTER-TOMOGRAPHY TRACER [I-123] IOMAZENIL

This study is based on the steady state method for the calculation of K(d) values recently described by Lassen (J. Cereb. Blood Flow Metab. 12 (1992), 709), in which a constant infusion of the examined nonradio active ligand is used with a bolus injection of tracer. Eight voluntee rs were examined twice, once without receptor blockade and once with a constant degree of partial blockade of the benzodiazepine receptors b y infusion of nonradioactive flumazenil (Lanexat) or midazolam (Dormic um). Single photon emission computer tomography and blood sampling wer e performed intermittently for 6 h after bolus injection of [I-123]iom azenil. The tracer in plasma was determined by high-pressure liquid ch romatography and also by a simple octanol extraction procedure. The fr ee concentration of flumazenil and midazolam in plasma water averaged 52% and 3.5% of that in whole plasma. The K(d) values for the entire c ortical rim for flumazenil were 7.4, 10.0, 10.3 and 17.7 nmol/I plasma water and, for midazolam, 73, 76, 58 and 30 nmol/l plasma water. The variation exceeds random methodological error and is probably due to i nterindividual differences in receptor affinity. The K(d) level of mid azolam is considerably higher than expected from the results of in vit ro studies.