Classification of benzodiazepine hypnotics in humans based on receptor occupancy theory.

Benzodiazepine (BZP) hypnotics are now classified into four groups according to their plasma elimination rates: ultrashort-, short-, intermediate-, and long-acting drugs. Since the specific binding affinities for the BZP receptor vary widely among the BZPs and their active metabolites, it may be more reasonable to correlate their pharmacological activities with the BZP receptor occupancy rather than with their plasma concentrations. The time courses of total plasma concentrations of BZPs and their active metabolites after a single oral administration were obtained from the literature, and their unbound concentrations (Cu) were calculated from the reported values of their plasma unbound fractions. The data of the receptor binding affinities of the BZPs, reported as dissociation constants (Kd) determined by in vitro binding experiments, were also obtained from the literature. Using these values, the time courses of receptor occupancies [Cu/(Kd + Cu) x 100%] were calculated for the various BZPs. A mutual competitive inhibition was considered in the case of the drugs that had active metabolites. Although plasma total and unbound concentration time profiles of the BZPs showed a wide variation, similar patterns were obtained for the time courses of the receptor occupancy among the BZPs in each group, indicating that the BZP hypnotics can be classified more conveniently based on receptor occupancy theory.