Benzodiazepine receptor equilibrium constants for flumazenil and midazolam determined in humans with the single photon emission computer tomography tracer [123I]iomazenil

Eur J Pharmacol. 1993 Nov 2;249(1):43-51. doi: 10.1016/0014-2999(93)90660-a.

Abstract

This study is based on the steady state method for the calculation of Kd values recently described by Lassen (J. Cereb. Blood Flow Metab. 12 (1992), 709), in which a constant infusion of the examined nonradioactive ligand is used with a bolus injection of tracer. Eight volunteers were examined twice, once without receptor blockade and once with a constant degree of partial blockade of the benzodiazepine receptors by infusion of nonradioactive flumazenil (Lanexat) or midazolam (Dormicum). Single photon emission computer tomography and blood sampling were performed intermittently for 6 h after bolus injection of [123I]iomazenil. The tracer in plasma was determined by high-pressure liquid chromatography and also by a simple octanol extraction procedure. The free concentration of flumazenil and midazolam in plasma water averaged 52% and 3.5% of that in whole plasma. The Kd values for the entire cortical rim for flumazenil were 7.4, 10.0, 10.3 and 17.7 nmol/l 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 interindividual differences in receptor affinity. The Kd level of midazolam is considerably higher than expected from the results of in vitro studies.

MeSH terms

  • Adolescent
  • Adult
  • Binding Sites
  • Blood Proteins / metabolism
  • Chromatography, High Pressure Liquid
  • Flumazenil / analogs & derivatives
  • Flumazenil / metabolism*
  • Flumazenil / pharmacology
  • Humans
  • Male
  • Midazolam / blood
  • Midazolam / metabolism*
  • Midazolam / pharmacology
  • Protein Binding
  • Receptors, GABA-A / drug effects
  • Receptors, GABA-A / metabolism*

Substances

  • Blood Proteins
  • Receptors, GABA-A
  • Flumazenil
  • iomazenil
  • Midazolam