RELATIONSHIP BETWEEN UNBOUND PLASMA-CONCENTRATIONS AND VARIOUS PSYCHOMOTOR AND SUBJECTIVE EFFECTS AFTER INTAKES OF DIAZEPAM AND FLUNITRAZEPAM

Unbound plasma concentrations of diazepam and flunitrazepam were relat ed to psychomotor and subjective effects of the two drugs. The interin dividual variability in plasma protein binding of both diazepam (98.5 +/- 0.14%) and flunitrazepam (84.5 +/- 1.2%) was relatively small, and high correlations were therefore observed between the individual unbo und and total drug plasma concentrations after a particular dose. Howe ver, poor correlations were seen between individual unbound drug plasm a concentrations and psychomotor or subjective effects. This observati on indicates that factors other than individual variability in drug pl asma concentration, account for the pronounced individual differences in, for example, psychomotor impairment frequently observed after inta ke of benzodiazepines. Furthermore, based on a linear relationship bet ween unbound drug plasma concentrations and increase in either complex choice or simple reaction time, the potency of flunitrazepam was calc ulated to be about seven times higher than the potency of diazepam. Th is is approximately two times higher than expected from the reported i n vitro affinity of the two drugs for the benzodiazepine receptor. Thi s finding may indicate that flunitrazepam may have a higher apparent i n vivo intrinsic efficacy than diazepam when assessed by psychomotor i mpairment.