非酒精性脂肪肝病理状态下的药物相互作用及相关机制研究

项目名称： 非酒精性脂肪肝病理状态下的药物相互作用及相关机制研究

项目编号： No.81202590

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 药物学、药理学

项目作者： 谢媛

作者单位： 中国药科大学

项目金额： 23万元

中文摘要： 非酒精性脂肪肝病理状态下，各项病理机制及药物代谢酶的改变，往往会影响药物在体内的处置过程；而脂肪肝常常伴随有高脂血症、糖尿病、高血压等诸多疾病的发生，使得病人的治疗相对复杂，因此，肝脏的不同病理程度和状态往往会影响相关治疗药物在体内的动力学过程，且须充分考虑病理状态下的药物/药物之间的相互作用（DDI）。本项目以非酒精性脂肪肝为基本病理模型，以临床常用的保肝药、高脂血症、高血压的治疗药物为探针，研究他们分别在病理状态和正常状态下的药物/药物相互作用，并通过对药物代谢酶和代谢组学的研究，验证科学假说：非酒精性脂肪肝病理状态会引起相关药物的药代动力学行为的改变和药物/药物相互作用的改变，这种改变可能受到保肝药治疗的调控，且变化程度和规律与肝损程度/药物代谢酶改变/内源性关键分子改变程度相关。通过建立药物的药代动力学行为的改变与病理程度/治疗效果之间的关联，为临床剂量调整和合理用药提供理论依据。

中文关键词： 姜黄素；非酒精性脂肪肝；药物相互作用；代谢；胰岛素抵抗

英文摘要： Liver disease threatened people's life all over the world because of the high fat and high fructose diet which might induce disorders of glucose and lipid metabolism, in accordance with high incidence of non-alcoholic fatty liver diseases (NAFLD). During non-alcoholic fatty liver disease, variations of pathomechanism and drug metabolism enzymes always influence the disposition of drugs in vivo. Since NAFLD are always companied by hyperlipemia, diabetes, or hypertension and so on, medication of NAFLD patients turns out to be complicated. The pharmacokinetic behaviors and drug/drug interactions (DDI) of these conventional drugs are probably different in NAFLD patients compared with healthy people. However, there was little reference pay attention to the influence of fatty liver to medication's pharmacokinetics, let alone the drug/drug interaction under fatty liver condition. Based on NAFLD model, this study choose conventional clinical used hepatoprotective agents, drugs of hyperlipemia and hypertension as probes to illustrate the differences of their pharmacokinetics and drug/drug interactions between pathological and healthy status, and further clarify the variation of drug metabolism enzymes in livers by PCR and Western Blot and the variation of endogenous molecules by metabonomics technology. Also, hepatocyt

英文关键词： Curcumin；NAFLD；DDI；metabolism；Insulin resistance