Development of a Physiologically Based Pharmacokinetic Model for Prediction of Ethanol Concentration-Time Profile in Different Organs.
Development of a Physiologically Based Pharmacokinetic Model for Prediction of Ethanol Concentration-Time Profile in Different Organs.
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开发基于生理学的药代动力学模型，用于预测不同器官中乙醇浓度-时间曲线。
DOI：
10.1093/alcalc/agaa129
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发表时间：
2021
期刊：
影响因子：
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通讯作者：
Akhlaghi,Fatemeh
中科院分区：
文献类型：
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作者：
Sadighi,Armin;Leggio,Lorenzo;Akhlaghi,Fatemeh
目的使用基于生理学的药代动力学（PBPK）建模方法来模拟在禁食和进食条件下消耗啤酒和威士忌后胃、十二指肠、血浆和其它组织中乙醇（EtOH）的浓度-时间曲线。方法使用完全集成到Simcyp Simulator® 15（Simcyp Ltd.，英国谢菲尔德）。结果Simcyp模拟结果显示，胃和十二指肠中乙醇浓度-时间曲线下面积（AUC）值与实测值相差≤ 2倍。此外，血浆中模拟的EtOH最大浓度（Cmax）、达到Cmax的时间（Tmax）和AUC与观察值相当。我们发现，肝脏暴露于最高浓度的乙醇，比其他器官更快（Cmax= 839.50 mg/L和Tmax= 0.53 h），而脑暴露的乙醇（AUC = 1139.43 mg·h/L）是所有其他器官中最高的。敏感性分析（SA）显示，直接比例的EtOH速率和程度的吸收与管理EtOH剂量和胃排空时间（GE）和稳态分布容积（Vss）的负相关性。结论目前的PBPK模型的方法可能有助于设计在酒精器官损伤或酒精-药物相互作用研究领域的体外实验。
AimsA physiologically based pharmacokinetic (PBPK) modeling approach was used to simulate the concentration-time profile of ethanol (EtOH) in stomach, duodenum, plasma and other tissues upon consumption of beer and whiskey under fasted and fed conditions.MethodsA full PBPK model was developed for EtOH using the advanced dissolution, absorption and metabolism (ADAM) model fully integrated into the Simcyp Simulator® 15 (Simcyp Ltd., Sheffield, UK). The prediction performance of the developed model was verified and the EtOH concentration-time profile in different organs was predicted.ResultsSimcyp simulation showed ≤ 2-fold difference in values of EtOH area under the concentration-time curve (AUC) in stomach and duodenum as compared to the observed values. Moreover, the simulated EtOH maximum concentration (Cmax), time to reach Cmax(Tmax) and AUC in plasma were comparable to the observed values. We showed that liver is exposed to the highest EtOH concentration, faster than other organs (Cmax= 839.50 mg/L and Tmax= 0.53 h), while brain exposure of EtOH (AUC = 1139.43 mg·h/L) is the highest among all other organs. Sensitivity analyses (SAs) showed direct proportion of EtOH rate and extent of absorption with administered EtOH dose and inverse relationship with gastric emptying time (GE) and steady-state volume of distribution (Vss).ConclusionsThe current PBPK model approach might help with designingin vitroexperiments in the area of alcohol organ damage or alcohol-drug interaction studies.