Regional Difference in the Effect of Influx/Efflux Transporters and Metabolic Enzymes on Intestinal Drug Absorption

流入/流出转运蛋白和代谢酶对肠道药物吸收影响的区域差异

• 批准号: 23590175
• 负责人: SHIRASAKA Yoshiyuki
• 金额: $ 3.33万
• 依托单位: Kanazawa University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2011
• 资助国家: 日本
• 起止时间: 2011 至 2013
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-23590175/
• 关键词: 薬学; 薬物動態学; 経口吸収; 徐放性製剤; トランスポーター; 代謝酵素; 薬物間相互作用; 生体分子

In the present study, we aimed to clarify the site-specific contribution of transporters and metabolic enzymes to the intestinal drug absorption. The rat in situ studies with talinolol and colchicine demonstrated site-specific drug absorption presumably due to differential expression and function of OATP and P-gp. Further analysis revealed presence of multiple binding sites on OATP2B1 with different affinity for drugs. Meanwhile, microsomal studies demonstrated that CYP3A5 genotype and expression level have a significant impact on inhibitory potency for CYP3A-catalyzed drug metabolism, but that the magnitude of its effect is inhibitor-substrate pair specific. The results of the study focusing on CYP2C19 show that, although metabolites contribute to in vivo DDIs, their relative abundance in circulation does not predict their contribution to in vivo DDI risk. These findings revealed involvement of influx/efflux transporters and metabolic enzymes in the intestinal drug absorption process.

在本研究中，我们的目的是澄清转运蛋白和代谢酶对肠道药物吸收的位点特异性贡献。他林洛尔和秋水仙碱的大鼠原位研究表明，可能由于OATP和P-gp的差异表达和功能，药物吸收具有位点特异性。进一步分析显示OATP 2B 1上存在多个结合位点，对药物具有不同的亲和力。同时，微粒体研究表明，CYP 3A 5基因型和表达水平对CYP 3A催化的药物代谢的抑制效力有显著影响，但其影响程度具有底物-底物对特异性。关注CYP 2C 19的研究结果表明，尽管代谢物有助于体内DDI，但其在循环中的相对丰度并不能预测其对体内DDI风险的贡献。这些发现揭示了内流/外排转运蛋白和代谢酶参与肠道药物吸收过程。

项目成果

Variability of Fruit Juice-Drug Interaction in Absorption Process Caused by Multiple Binding Sites on OATP2B1

OATP2B1 上多个结合位点引起的果汁-药物相互作用在吸收过程中的变化

• 发表时间: 2011
• 作者: Takanori Mori;Yoshiyuki Shirasaka;Megumi Shichiri;Satoshi Koyama;Yukiko Murata;Yusuke Hoshino;Takeo Nakanishi;and Ikumi Tamai
• 通讯作者: and Ikumi Tamai

MDR1 is Related to Intestinal Epithelial Injury Induced by Acetylsalicylic Acid

• DOI: 10.1159/000354497
• 发表时间: 2013-01-01
• 期刊: CELLULAR PHYSIOLOGY AND BIOCHEMISTRY
• 作者: Kugai, Munehiro;Uchiyama, Kazuhiko;Itoh, Yoshito
• 通讯作者: Itoh, Yoshito

Substrate-Dependent Drug-Grapefruit Juice Interactions Caused by Multiple Binding Sites on OATP2B1

OATP2B1 上多个结合位点引起的底物依赖性药物-葡萄柚汁相互作用

• 发表时间: 2012
• 作者: Takanori Mori;Yoshiyuki Shirasaka;Yukiko Murata;Takeo Nakanishi and Ikumi Tamai
• 通讯作者: Takeo Nakanishi and Ikumi Tamai

Drug Absorption and Interaction on Intestinal Transporters

药物吸收和肠道转运蛋白的相互作用

• 发表时间: 2011
• 作者: Ikumi Tamai;Yoshiyuki Shirasaka;and Takeo Nakanishi
• 通讯作者: and Takeo Nakanishi

Differential Interaction of Fruit Juices with Transporter-Mediated Absorption of Drugs

果汁与转运蛋白介导的药物吸收的差异相互作用

• 发表时间: 2011
• 作者: Megumi Shichiri;Yoshiyuki Shirasaka;Takanori Mori;Takeo Nakanishi;and Ikumi Tamai
• 通讯作者: and Ikumi Tamai