[關(guān)鍵詞]
[摘要]
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?。╩elperone)、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)間過程。方法 通過對(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。
[Key word]
[Abstract]
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.
[中圖分類號(hào)]
R971
[基金項(xiàng)目]
國(guó)家自然科學(xué)基金資助項(xiàng)目(81973295)