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

药物相互作用的定量评估和处方支持系统的开发以避免不良反应

• 批准号: 10357022
• 负责人: IGA Tatsuji
• 金额: $ 20.93万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10357022/
• 关键词: drug interaction; avoidance of side effects; Prescription-inspection supporting system; drug information; clinical trials; pharmacogenetics; 処方オーダリング; クリアランス理論; P-糖タンパク質; グレープフルーツジュース; データベース

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

1)药物相互作用机制：进行药物-葡萄汁（GFJ）相互作用研究，以阐明药物在肠道组织中相互作用的机制。我们已经发现，GFJ组分，二羟基vergamotine，抑制P-糖蛋白的流出活性。因此，根据对Pglycoproptein和P450酶的这种抑制机制，GFJ可以促进药物的吸收，从而提高药物的血药浓度。2）建立临床前阶段药物相互作用的预测方法和临床试验的剂量设定：使用钙受体阻滞剂非洛地平和免疫抑制剂环孢素作为模型化合物，进行建模分析以定量预测药物相互作用。我们试图预测的贡献，肝脏和肠道的药物相互作用的基础上清除理论，在体内和体外实验中使用大鼠。因此，成功地预测了d的增加 ...更多信息 通过使用一种新的预测肝脏和肠道中抑制剂浓度的方法计算这些组织中的药物浓度，从而确定血液中的药物浓度。此外，在本研究中，可以估计当联合施用抑制剂时人体血液中药物浓度的增加。3）遗传多态性的研究：关于CYP 2C 19，我们发现显示wt/m1和wt/m2的人的清除值，这些人通常被归类为快代谢者（EM），福尔斯介于EM和弱代谢者（PM）的清除率值之间，表明杂合多态性导致代谢活性降低。在胃溃疡患者中，以药物标签中规定的常规剂量给予奥美拉唑的临床效果（使用内窥镜检查溃疡改善）对于PM为83%，对于EM为32%，这应该是PM清除率降低的表现。PM中溃疡愈合所需的时间也较短。4）构建关于剂量设置和药物选择的信息，以避免市场上药物的相互作用：我们对药物相互作用的临床病例进行了回顾性调查，并建立了剂量设定方法，5）开发软件以搜索关于避免药物相互作用的药物信息：我们建立了一个药物相互作用的数据库，通过它我们可以快速搜索药物相互作用的组合。然后在个人计算机上实现软件，以基于上述数据库分析可能的药物相互作用，该数据库可以容易地在临床环境中使用。6）建立和评价订单输入系统，以提供关于药物相互作用的药物信息：通过将上述软件结合到传统的订单输入系统中，我们在东京大学医院开发了一个用于药物相互作用的订单输入/处方审核系统。少

项目成果

澤田康文: "Contribution of P-glycoprotein to bunitrolol efflux across blood-brain barrier."Biopharm. Drug Dispos.. 20. 85-90 (1999)

Yasufumi Sawada：“P-糖蛋白对联硝洛尔穿过血脑屏障流出的贡献。”Biopharm. Drug Dispos.. 20. 85-90 (1999)

Higuchi, S.: "The Effects of Genetic Polymorphisms of CYP2C9 and CYP2C19 on Phenytoin Metabolism in Japanese Adult Patients with Epilepsy : Studies in Stereoselective Hydroxylation and Population Pharmacokinetics."Epilepsia. 39. 1317-1323 (1998)

Higuchi, S.：“CYP2C9 和 CYP2C19 的遗传多态性对日本成人癫痫患者苯妥英代谢的影响：立体选择性羟基化和群体药代动力学的研究。”癫痫。

伊賀立ニ,沢田康文,その他: "Inhibition of vinblastin efflux mediated by P-glycoprotein by grapefruit juice components in Caco-2 cells"Biol. Pharm. Bull.. 21. 1062-1066 (1998)

Ni Igatatsu，Yasufumi Sawada 等：“Caco-2 细胞中葡萄柚汁成分对长春花素外流的抑制”Biol Pharm. 21. 1062-1066 (1998)

伊賀立二: "Quantitative prediction of metabolic inhibition of midazolam by itraconazole and ketoconazole in rats : implication of concentrative uptake of inhibitors into liver."Drug Metab. Dispos.. 27. 395-402 (1999)

Tatsuji Iga：“伊曲康唑和酮康唑对大鼠咪达唑仑代谢抑制的定量预测：抑制剂集中摄取到肝脏的含义。”Drug Metab. 27. 395-402 (1999)

澤田康文: "Inhibition of vinblastine efflux mediated by P-glycoprotein by grapegruit juice components in Caco-2 cells."Biol. Pharm. Bull.. 21. 1062-1066 (1998)

Yasufumi Sawada：“Caco-2 细胞中葡萄柚汁成分对 P-糖蛋白介导的长春花碱流出的抑制。”Biol. Pharm. Bull. 21. 1062-1066 (1998)