目的 模拟分析10种抗精神病药物氟哌啶醇（haloperidol）、舒必利（sulpiride）、美哌隆（melperone）、氯氮平（clozapine）、喹硫平（quetiapine）、利培酮（risperidone）、齐拉西酮（ziprasidone）、瑞莫必利（remoxipride）、氨磺必利（amisulpride）、雷氯必利（raclopride）口服给药后在人体内对多巴胺D₂受体（DRD₂）占有的时间过程。方法 通过对10种抗精神病药物的口服给药和静脉给药的药动学数据模拟计算获取建模的药动学（PK）参数；通过已发表的文献数据计算获取10种抗精神病药物的结合动力学（BK）参数和细胞内DRD₂受体合成动力学（TK）参数；基于获取的PK、BK、TK参数建立10种抗精神病药物的DRD₂受体占有率数学计算模型（PK-BK-TK模型）。结果 已上市的9种（不包含雷氯必利）抗精神病药物在临床推荐剂量下对DRD₂的最大受体占有率均在65%以上，预测的DRD₂受体占有率曲线与其临床药效持续时间有良好的一致性；雷氯必利的合理给药剂量为2mg。结论 利用PK-BK-TK数学模型能准确预测抗精神病药物口服后在人体内对DRD₂受体的占有过程。该模型可为评估化合物在体内拮抗DRD₂受体的活性与潜在毒性提供一种新的研究思路和方法。

Objective To simulate the time course of occupancy rates of 10 antipsychotic drugs including haloperidol, sulpiride, melperone, clozapine, quetiapine, risperidone, ziprasidone, remoxipride, amisulpride and raclopride on the dopamine D₂ receptors (DRD₂) in vivo. Methods The modeled pharmacokinetic parameters (PK parameters) of 10 antipsychotic drugs were obtained by simulating and calculating the pharmacokinetic data of the oral and intravenous administration; The binding kinetic parameters (BK parameters) and the intracellular DRD₂ receptor synthesising kinetic parameters (TK parameters) of 10 antipsychotic drugs were obtained based on published literature data. Based on the acquired PK, BK and TK parameters we can establish a mathematical calculation model (PK-BK-TK model) for receptor occupancy of 10 antipsychotic drugs. Results The maximum receptor occupancy rates of all the nine antipsychotic drugs at the clinically recommended doses were above 65%, and the predicted curves of receptor occupancy rate in vivo were consistent with their duration of clinical efficacy. The reasonable dose of raclopride was 2 mg. Conclusion The PK-BK-TK mathematical model can effectively evaluate the receptor occupation process in vivo after oral antipsychotic drugs, which provides a new research idea and method for assessing the activity and potential toxicity of compounds antagonize DRD₂ receptors in vivo.

R971

国家自然科学基金资助项目（81973295）