基于转运蛋白的代谢性数字肝生理模型预测普伐他汀、匹伐他汀与环孢素的药代动力学相互作用
Prediction of the pharmacokinetic drug-drug interaction of pravastatin and pitavastatin with cyclosporine by a digital liver model based on metabolism and transporter
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摘要:
基于转运蛋白的代谢性数字肝生理模型 (digital liver model, DLM) 程序由VBA (visual basic aplication) 编辑而成, 整合了代谢酶、转运蛋白多态性信息及动物生理学参数和中国人口统计学数据, 依据离体或在体的药代动力学实验结果模拟预测候选药物在动物及中国人肝脏内的代谢清除过程, 估算药物清除率及药物相互作用。本文应用该模型模拟预测了普伐他汀、匹伐他汀的清除率及与环孢素的相互作用。83.3% (5/6) 同一种属内参数预测平均值在文献值的2倍范围内, 且能够很好地预测药物在临床上的相互作用趋势, 对指明试验方向、降低临床试验风险有重要意义。
Abstract:Information of metabolic enzymes and transporters, physiological parameters of animals and demography of Chinese people were integrated to establish a digital liver model (DLM) based on metabolism and transporter and coded with VBA. Clearance and drug-drug interaction (DDI) of candidate drugs in animal and human could be predicted based on the pharmacokinetic data obtained from in vitro and in vivo experiments. Pravastatin and pitavastatin were selected as the samples to examine this model, where their clearance and their DDI with cyclosporine were predicted. The results showed that the predicted values of median parameters in same species were within twofold of observed values for 83.3% (5/6). The program’s successful prediction in DDI tendency might indicate its application in optimizing the dosage regimen and reducing the risk of clinical trial.
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