Relationship between unbound plasma concentrations and various psychomotor and subjective effects after intakes of...

Unbound plasma concentrations of diazepam and flunitrazepam were related to psychomotor and subjective effects of the two drugs. The interindividual 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 unbound and total drug plasma concentrations after a particular dose. However, poor correlations were seen between individual unbound drug plasma concentrations and psychomotor or subjective effects. This observation indicates that factors other than individual variability in drug plasma concentration, account for the pronounced individual differences in, for example, psychomotor impairment frequently observed after intake of benzodiazepines. Furthermore, based on a linear relationship between unbound drug plasma concentrations and increase in either complex choice or simple reaction time, the potency of flunitrazepam was calculated to be about seven times higher than the potency of diazepam. This is approximately two times higher than expected from the reported in vitro affinity of the two drugs for the benzodiazepine receptor. This finding may indicate that flunitrazepam may have a higher apparent in vivo intrinsic efficacy than diazepam when assessed by psychomotor impairment.