目的 模擬分析10種抗精神病藥物氟哌啶醇（haloperidol）、舒必利（sulpiride）、美哌隆（melperone）、氯氮平（clozapine）、喹硫平（quetiapine）、利培酮（risperidone）、齊拉西酮（ziprasidone）、瑞莫必利（remoxipride）、氨磺必利（amisulpride）、雷氯必利（raclopride）口服給藥后在人體內(nèi)對(duì)多巴胺D₂受體（DRD₂）占有的時(shí)間過(guò)程。方法 通過(guò)對(duì)10種抗精神病藥物的口服給藥和靜脈給藥的藥動(dòng)學(xué)數(shù)據(jù)模擬計(jì)算獲取建模的藥動(dòng)學(xué)（PK）參數(shù)；通過(guò)已發(fā)表的文獻(xiàn)數(shù)據(jù)計(jì)算獲取10種抗精神病藥物的結(jié)合動(dòng)力學(xué)（BK）參數(shù)和細(xì)胞內(nèi)DRD₂受體合成動(dòng)力學(xué)（TK）參數(shù)；基于獲取的PK、BK、TK參數(shù)建立10種抗精神病藥物的DRD₂受體占有率數(shù)學(xué)計(jì)算模型（PK-BK-TK模型）。結(jié)果 已上市的9種（不包含雷氯必利）抗精神病藥物在臨床推薦劑量下對(duì)DRD₂的最大受體占有率均在65%以上，預(yù)測(cè)的DRD₂受體占有率曲線與其臨床藥效持續(xù)時(shí)間有良好的一致性；雷氯必利的合理給藥劑量為2mg。結(jié)論 利用PK-BK-TK數(shù)學(xué)模型能準(zhǔn)確預(yù)測(cè)抗精神病藥物口服后在人體內(nèi)對(duì)DRD₂受體的占有過(guò)程。該模型可為評(píng)估化合物在體內(nèi)拮抗DRD₂受體的活性與潛在毒性提供一種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

國(guó)家自然科學(xué)基金資助項(xiàng)目（81973295）