J. Ingum et al., RELATIONSHIP BETWEEN UNBOUND PLASMA-CONCENTRATIONS AND VARIOUS PSYCHOMOTOR AND SUBJECTIVE EFFECTS AFTER INTAKES OF DIAZEPAM AND FLUNITRAZEPAM, International clinical psychopharmacology, 9(2), 1994, pp. 115-121
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.