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.