抄録
Antipsychotic drugs have been widely used in humans for the treatment of schizophrenic psychosis. It is widely accepted that the pharmacological activities of antipsychotic drugs are best associated with its dopamine D2 receptor blockade. The usual therapeutic doses vary to a high extent among the antipsychotic drugs with the maximum of about 500-fold difference, despite of the same clinical improvement. In order to clarify the mechanism of this difference, we analyzed retrospectively the pharmacotherapeutic effects of antipsychotic drugs based on the receptor occupancy theory. Since the antipsychotic drugs readily transfer across the brain cell membranes, the dopamine D2 receptor occupancies of various drugs were calculated by using both their unbound concentrations in plasma and dissociation constants(Kd) for dopamine D2 receptor, and then compared with those determined by PET. The calculated dopamine D2 receptor occupancies of antipsychotic drugs which had no active metabolites were almost constant (76.4±15.0%) and corresponded to those determined by PET (80.0±7.6%). On the other hand, the calculated receptor occupancies of antipsychotic drugs which had active metabolites varied between 0.8 to 35% because of no consideration of active metabolites. However, those determined by PET were stable (79.8±4.1%). This finding indicated that the usual doses of antipsychotic drugs allowed to get about 79% as the optimum dopamine D2 receptor occupancy. Furthermore, the simulation of effect-receptor occupancy curves based on the ternary complex model indicated that the large receptor occupancy was necessary for sufficient therapeutic effect of antipsychotic drugs. Based on these findings, we could develop a methodology for estimating the rational usual dose of a newly developed drug by using Kd and data on pharmacokinetics in phase I clinical study.
