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：通过药物与葡萄汁(GFJ)的相互作用研究，阐明药物在肠道组织中的作用机制。我们发现GFJ的一个成分，二羟基藜芦醇，可以抑制P-糖蛋白的外排活性。2)临床前期药物相互作用预测方法的建立和临床试验用药剂量设置的建立：以钙拮抗剂非洛地平和免疫抑制剂环孢素为模型化合物，进行了定量预测药物相互作用的模拟分析。我们试图根据体内和体外实验中的清除理论预测肝脏和肠道在药物相互作用中的作用。结果，成功地预测了d-…的增长。通过使用一种新的方法预测这些组织中的抑制剂浓度来计算肝脏和肠道中的药物浓度，从而增加血液中的RUG浓度。3)基因多态研究：关于CYP2C19，我们发现显示wt/m1和wt/m2的人的清除值介于EM和劣代谢物(PM)的清除值之间，这表明杂合性多态导致代谢活性降低。在胃溃疡患者中，药物标签上标明的常规剂量的奥美拉唑的临床有效率(内窥镜检查溃疡好转)在PM组为83%，EM组为32%，这应该是PM清除率降低的表现在PM中，溃疡愈合所需的时间也较短。4)构建避免市场上药物相互作用的剂量设置和药物选择信息：我们对药物相互作用的临床病例进行了回顾性调查，并建立了剂量设置方法，用于可能与联合用药药物相互作用的特定药物交替使用。5)药物相互作用避免信息搜索软件的开发：我们建立了药物相互作用药物信息数据库，通过该数据库可以快速搜索药物相互作用的组合。6)建立和评价了药品相互作用订单录入系统的建立和评价：将上述软件整合到传统的药品相互作用订单录入系统中，开发了东京大学医院药品相互作用订单录入/处方审核系统。较少

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