Diazepam: prediction of pharmacodynamics from pharmacokinetics

The use of a pharmacokinetic/pharmacodynamic/receptor binding model to predict the onset and duration of the pharmacological effect of diazepam was explored. The analysis examined the effects of diazepam (0.28 mg/kg) on the wheel-tracking and digit-symbol substitution performance of young healthy adults. Both free-plasma drug concentration and relative amount of diazepam bound to the benzodiazepine receptor were calculated and compared to the behavioral measures across time. Performance was more significant correlated with relative receptor occupancy (RRO) than with unbound plasma-drug levels. For both tasks hysteresis plots indicated greater similarity between time profiles of performance and RRO than between those of performance and blood concentration alone. These results provide support for the inclusion of both receptor binding kinetics and plasma pharmacokinetics as the bases for the prediction of the pharmacologic activity of diazepam.