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目的:建立阿托伐他汀在健康人群中的生理药动学模型,预测其在人体内的组织分布及特征,为优化阿托伐他汀的治疗方案提供依据。方法:文献中获取关于阿托伐他汀理化参数及体外酶促动力学参数及数值。结合药物理化参数得到组织-血浆分配平衡系数(Kp),应用GastroPlus软件,建立阿托伐他汀的生理药动学模型,验证模型有效性,预测各器官组织中阿托伐他汀的经时变化,并运用模型预测阿托伐他汀在儿童及老年人群体内各器官组织中药物的经时变化,为个体化用药提供依据。结果:经验证,模型的有效性良好。阿托伐他汀在14个组织室均有分布,其中在血液、皮肤、肺中分布较高,Cmax分别为6.04,1.70,1.32 ng·ml-1;在脂肪和脑中分布较低,Cmax分别为0.31,0.33 ng·ml-1。儿童及老年人群体各器官组织阿托伐他汀的经时变化模型预测发现,儿童血液、皮肤、肺分布较高,Cmax分别为12.49,3.52,2.73 ng·ml-1;脑分布最低,Cmax为0.69ng·ml-1;老年血液、皮肤、肺分布较高,Cmax分别为8.97,2.53,1.96 ng·ml-1;肌肉分布最低,Cmax为0.63 ng·ml-1。结论:儿童及老年体内阿托伐他汀不同组织分布的Cmax为青年健康人群的两倍,显示年龄影响阿托伐他汀在体内的分布,儿童和老年人应用阿托伐他汀,存在较高发生不良反应的风险,应根据生理生化指标调整剂量,避免不良反应的发生。
OBJECTIVE: To establish a pharmacokinetic model of atorvastatin in healthy volunteers and to predict the tissue distribution and characteristics of atorvastatin in human, so as to provide a basis for optimizing atorvastatin treatment. Methods: The literature for Atovavastatin physical and chemical parameters and in vitro enzymatic kinetic parameters and values. The pharmacokinetic parameters were used to get the tissue-to-plasma partition coefficient (Kp). GastroPlus software was used to establish the pharmacokinetic model of atorvastatin. The model was validated to predict the changes of atorvastatin in various organs and tissues. And use the model to predict atorvastatin in children and the elderly in various organs and tissues of the organism in time changes, provide the basis for individualized medication. Results: The results show that the model is effective. Atorvastatin was distributed in 14 tissue compartments with high distribution in blood, skin and lungs, with Cmax of 6.04,1.70 and 1.32 ng · ml-1, respectively. The distribution of atorvastatin was lower in fat and brain, and Cmax was 0.31 and 0.33 ng · ml-1. The changes of atorvastatin in various organs and tissues of children and the elderly predicted that the distributions of blood, skin and lungs were higher in children with Cmax of 12.49, 3.52 and 2.73 ng · ml-1, respectively. The distribution of Cmax was 0.69ng · ml-1. The distribution of blood, skin and lung were higher in aged patients with Cmax of 8.97, 2.53 and 1.96 ng · ml-1, respectively. The distribution of muscle was the lowest with a Cmax of 0.63 ng · ml-1. CONCLUSION: Cmax for distribution of atorvastatin in children and the elderly is twice as high as that in healthy young adults, indicating that age affects the distribution of atorvastatin in the body and that atorvastatin is used in children and the elderly, with a high prevalence of adverse events The risk of reaction should be based on physiological and biochemical indicators to adjust the dose to avoid the occurrence of adverse reactions.