药物/内源性物质脑内处置高度依赖于脑内药物转运体和代谢酶间有序协同作用（脑药物转运体-代谢酶联盟）。鉴于肝损伤显著改变脑内药物转运体(P-GP、BCRP、Oat3和Oct3)和代谢酶（Cyp2d4和Ugt1a）表达，以及增加脑内5-羟色胺、色氨酸、多巴胺和5-吲哚乙酸等浓度的事实，提出肝损伤改变脑内药物转运体和代谢酶的功能与表达，引起脑药物转运体-代谢酶联盟失衡，进而改变脑内药物处置和中枢活性，其改变程度是药物转运体和代谢酶改变整合效应的推论。以上述药物转运体和代谢酶为靶点，用硫代乙酰胺和胆管结扎诱导肝损伤大鼠，结合细胞实验，研究：①肝损伤引起脑药物转运体-代谢酶联盟失衡及机制；②脑内药物转运体和代谢酶改变各自对文拉法辛等药物脑内处置贡献和整合效应；③这种联盟失衡对脑内5-羟色胺等物质浓度紊乱的贡献。其成果有助于阐明脑药物转运体-代谢酶失衡在肝性脑病中作用，药物脑内处置和中枢不良反应预测。

Brain disposition of drugs and endogenous substances is highly dependent on orderly coordination of drug transporters and drug metabolism enzymes (i.e. brain transporter-enzyme interplay). Based on the facts that liver failure remarkably altered expression of drug transporters (P-GP, BCRP, Oat3 and Oct3) and enzymes (Cyp2d4 and Ugt1a) and increased levels of some endogenous substances (such as tryptophan, 5-hydroxytryptamine, dopamine and 5-hydroxyindoleacetic acid) in brain, we proposed following hypothesis. “Liver failure altered expression and function of drug transporters and enzymes in brain, leading to disturbance of transporter-enzyme interplay, in turn altering brain disposition of drugs and their CNS efficacy. Extent of the alterations was integrated effects of the altered drug transporters and enzymes”. Here, we used liver failure rats induced by thioacetamide and bile duct-ligation as well as in vitro cell model to investigate: 1. alterations in expression and function of drug transporters (P-GP, BCRP, Oat3 and Oct3) and enzymes (Cyp2d4 and Ugt1a) in brain by liver failure and their mechanisms which were involved in these alterations; 2. indidivual contribution of alterations in drug transporters and enzymes by liver failure to the alterations in brain disposition of drugs (such as venlafaxine) and CNS activity as well as their integrated effect; 3. contribution of the disordered transporter-enzyme interplay to disturbance of some endogenous substances (such as tryptophan and 5-hydroxytryptamine) in brain. These results may also highlight roles of the disordered transporter-enzyme interplay in hepatic encephalopathy, prediction of brain disposition of drugs and their central adverse reactions.