Quantitative evaluation of drug interactions and development of a prescription-supporting system for the avoidance of adverse effects

1)药物相互作用机制：开展药物-葡萄果汁（GFJ）相互作用研究，阐明药物在肠道组织中的相互作用机制。我们发现，一种GFJ成分，二羟基维甘油酯，抑制p -糖蛋白的外排活性。由此可见，根据这种对P450酶和糖蛋白的抑制机制，GFJ增强了药物对药物的吸收，从而提高了药物的血药浓度。2)建立临床前阶段药物相互作用预测方法及临床试验剂量设置：以钙受体阻滞剂非洛地平和免疫抑制剂环孢素为模型化合物，进行模型分析，定量预测药物相互作用。我们试图预测肝脏和肠道在药物相互作用中的贡献基于清除理论从体内和体外实验的大鼠。结果，通过计算肝脏和肠道中的药物浓度，使用一种预测这些组织中抑制剂浓度的新方法，成功地预测了血液中d…More药物浓度的增加。此外，在这项研究中，可以估计当一种抑制剂同时使用时，人体血液中药物浓度的增加。3)遗传多态性的研究：CYP2C19，我们发现通常被归类为广泛代谢者（EM）的wt/m1和wt/m2人群的清除率值介于EM和差代谢者（PM）之间，表明杂合多态性导致代谢活性降低。在胃溃疡患者中，奥美拉唑的临床疗效（内窥镜检查溃疡改善情况），按照药物标签上的指示，按常规剂量给予奥美拉唑，PM为83%，EM为32%，这应该是PM清除率降低的表现。4)建立剂量设置和药物选择信息，避免市场上药物相互作用：我们对药物相互作用的临床病例进行了回顾性调查，建立了剂量设置方法，用于替代可能与共给药药物相互作用的特定药物。5)药物相互作用回避药物信息搜索软件开发：建立药物相互作用药物信息数据库，快速搜索药物相互作用组合。然后实施个人电脑软件，以上述数据库为基础分析可能的药物相互作用，这可以很容易地在临床环境中使用。6)提供药物相互作用信息的订单录入系统的建立与评价：我们将上述软件整合到常规的订单录入系统中，开发了东京大学医院的药物相互作用订单录入/处方审核系统。少

1) Mechanism of drug interactions : Drug-grape fruit juice (GFJ) interaction studies were undertaken to clarify the mechanism of drug interactions at the gut tissue. We have found that a GFJ component, dihydroxy vergamotine, inhibited the efflux activity of P-glyco-protein. It was thus suggested that, according to this inhibitory mechanism on Pglycoproptein as well as on P450 enzymes, GFJ enhances the drug absorption of drugs, by which plasma concentrations of drugs may inrease.2) Establishment of a prediction method of drug interactions in preclinical phases and dose setting for clinical trials : Modelling analysis was carried out to predict drug interactions quantitatively, using a Ca-blocker, felodipine, and an immunosuppresant, cyclosporine, as model compounds. We attempted to predict the contributions of the liver and gut in drug interactions based on clearance theory from in vivo and in vitro experiments using rats. As a result, it has been successful to predict the increase in d … More rug concentrations in blood by calculating drug concentrations in the liver and gut using a new method of predicting inhibitor concentrations in these tissues. Moreover, it has become possible in this study to estimate the increase in drug concentrations in blood in humans when an inhibitor is coadministered.3) Investigation of genetic polymorphism : With regard to CYP2C19, we found that the clearance value of people showing wt/m1 and wt/m2, which have been conventionally classified as extensive metabolizer (EM), falls between the clearance values in EM and poor metabolizer (PM), indicating that heterozygous polymoriphisms lead to the reduction of metabolic activities. In patients with gastric ulcer, clinical effect (examination of ulcer improvement using an endoscope) of omeprazole, given at regular doses indicated in drug labelling, was 83% for PM and 32% for EM, which should be the manifestation of reduced clearance in PM. The short period of time required for ulcer healing was also shorter in PM.4) Construction of information on dose settings and choice of medicine to avoid interactions of drugs in the market : We conducted a retrospective survey of clinical cases for drug interactions, and established a dose setting method, be used alternatively for particular drugs which may interact with co-administered drugs.5) Development of software to search drug information on drug interaction avoidance : We created a database of drug information on drug interactions, by which we can rapidly search the combination of drug interactions. Software for personal computers was then implemented to analyze possible drug interactions based on the above database, which can be easily utilized in clinical settings.6) Establishment and evaluation of an order entry system to provide drug information on drug interactions : By incorporating the above mentioned software into the conventional order entry system, we developed an order entry/prescription auditing system for drug interactions in the University of Tokyo Hospital. Less