Many benzodiazepines (BZPs) are now used as anxiolytics with nearly 200-fold variety of therapeutic doses. The variation of the doses of BZPs is due to dierences both in their pharmacokinetics and in their receptor binding characteristics. The purpose of this study is to clarify the mechanism of the dierences in therapeutic dose by retrospective analyses and to develop a system for the quantitative estimation of optimal doses of BZPs.
The values of receptor dissociation constant (K d ), which indicates the binding anity of each BZP at the receptor site, were obtained from a number of works based on in vitro binding experiments. The plasma unbound concentrations of the BZPs and their active metabolites were calculated using the reported values of their total plasma concentrations after average oral doses of the BZPs and the values of their plasma unbound fractions, which were also taken from the literature.
There were log-linear relationships between the K d values of BZPs and their average therapeutic doses or maximum plasma concentrations, but the correlation coecients were relatively small (r50ยด77). In contrast, a good log-linearity (r=0ยด96) was observed in the correlation between their K d values and the eective plasma unbound concentrations considering the active metabolites. This ยฎnding indicates that the receptor occupancy after administration of therapeutic dose of BZPs is consistent (52ยด3+3ยด2%) among the BZPs. In this study, we also develop a possible system for estimating the appropriate doses of BZPs based on receptor occupancy theory. &1997 by John Wiley & Sons, Ltd.