Drug Toxicity Induced by Alteration of Transporter Activity

转运蛋白活性改变引起的药物毒性

• 批准号: 15390051
• 负责人: TAMAI Ikumi
• 金额: $ 9.6万
• 依托单位: TOKYO UNIVERSITY OF SCIENCE
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15390051/
• 关键词: Transporter; Membrane transport; Toxicity; Drug interaction; Genetic polymorphism; Nuclear receptor; Regulation of gene expression; 肝毒性; 肝取り込み; OATP; 有機アニオントランスポーター; 胆汁中排泄; 発現調節機構; 尿中排泄; 有機カチオントランスポーター

Drug toxicity is a significant problem in developing drugs, because the toxicity induced by drugs or drug candidates will lead to the removal from the market or termination of drug development, even though the compound exhibits excellent pharmacological effect.To evaluate possible toxicity of drugs or drug candidates, it will be essential to accumulate more information on the mechanisms of occurrence of drug-induced toxicity. As one of possible mechanisms, transporter proteins should be involved, because transporters significantly affect the cellular concentration and the pharmacokinetic profiling of drugs. Here, we studied the transport mechanisms of drugs by focusing on several tissues, including intestine, liver, kidney, brain, testis, tumor, and blood cells. As the results, we succeeded to identify SLCO2B1(OATP-B) as the transporter involved in intestinal absorption of anionic drugs, in functionally pH dependent manners. Furthermore, we studied the brain penetration of H1-antagonists and the permeability of the drug across the blood-brain barrier was strictly regulated by transporters like P-glycoprotein and molecularly-unknown cation transporters. In the case of kidney, apically and basolaterally expressed transporters like OCTs and OCTNs were studied and their pharmacological relevance was suggested. Next, we evaluated the effect of genetic polymorphisms of transporter genes on the transport activity. SLCO1B1(OATP-C) is a hepatic transporter important for hepatic uptake of drugs and the genetic variants OATP-C^*15 exhibited lowered transport activity than wild one for toxicologically important drugs like troglitazone, irinotecan and others. Furthermore, we studied the regulation mechanism of the gene expression of hepatic transporters by focusing on nuclear receptor FXR. These studies clarified that there are many factors that affect apparent activity of transporter and we need to study further the clinical.

药物毒性是药物开发中的一个重要问题，因为药物或候选药物引起的毒性会导致药物退出市场或终止药物开发，即使该化合物具有良好的药理作用。为了评估药物或候选药物可能的毒性，积累更多关于药物诱导毒性发生机制的信息是至关重要的。作为一种可能的机制，转运蛋白应该参与其中，因为转运蛋白显著影响药物的细胞浓度和药代动力学特征。在这里，我们重点研究了药物的转运机制，包括肠、肝、肾、脑、睾丸、肿瘤和血细胞。结果，我们成功地鉴定出SLCO2B1（OATP-B）是参与阴离子药物肠道吸收的转运蛋白，其功能依赖于pH值。此外，我们研究了h1拮抗剂的脑穿透性，发现药物穿过血脑屏障的通透性受到转运蛋白如p -糖蛋白和分子未知的阳离子转运蛋白的严格调节。在肾脏的情况下，研究了OCTs和OCTNs等顶端和基底侧表达的转运蛋白，并提出了它们的药理学相关性。接下来，我们评估了转运基因的遗传多态性对转运活性的影响。SLCO1B1（OATP-C）是一种肝脏转运蛋白，对药物的肝脏摄取很重要，基因变异OATP-C^*15对曲格列酮、伊立替康等重要毒理学药物的转运活性比野生型低。此外，我们以核受体FXR为重点，研究了肝脏转运体基因表达的调控机制。这些研究表明，影响转运蛋白表观活性的因素很多，需要进一步的临床研究。

项目成果

Involvement of human organic anion transporting polypeptide OATP-B (SLC21A9) in pH-dependent transport across intestinal apical membrane

• DOI: 10.1124/jpet.103.051300
• 发表时间: 2003-08-01
• 期刊: JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
• 影响因子: 3.5
• 作者: Kobayashi, D;Nozawa, T;Tamai, I
• 通讯作者: Tamai, I

Functional characterization of pH-sensitive organic anion transporting polypeptide OATP-B in human

• DOI: 10.1124/jpet.103.060194
• 发表时间: 2004-02-01
• 期刊: JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
• 影响因子: 3.5
• 作者: Nozawa, T;Imai, K;Tamai, I
• 通讯作者: Tamai, I

Regulation of drug transporters by the farnesoid X receptor in mice.

• DOI: 10.1021/mp0499656
• 发表时间: 2004-06
• 期刊: Molecular pharmaceutics
• 影响因子: 4.9
• 作者: Tomoji Maeda;M. Miyata;T. Yotsumoto;Daisuke Kobayashi;T. Nozawa;Keisuke Toyama;F. Gonzalez;Y. Yamazoe;I. Tamai

Role of organic anion transporter OATP1B1 (OATP-C) in hepatic uptake of irinotecan and its active metabolite, 7-ethyl-10-hydroxycamptothecin: In vitro evidence and effect of single nucleotide polymorphisms

• DOI: 10.1124/dmd.104.001909
• 发表时间: 2005-03-01
• 期刊: DRUG METABOLISM AND DISPOSITION
• 影响因子: 3.9
• 作者: Nozawa, T;Minami, H;Tamai, I
• 通讯作者: Tamai, I

Expression of organic cation transporter OCTN1 in hematopoietic cells during erythroid differentiation

• DOI: 10.1016/j.exphem.2004.08.009
• 发表时间: 2004-12-01
• 期刊: EXPERIMENTAL HEMATOLOGY
• 影响因子: 2.6
• 作者: Kobayashi, D;Aizawa, S;Tamai, I
• 通讯作者: Tamai, I