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Studies on the impact of the drug transporter OATP1B3 on the pancreatic effects of CCK-8 and sulfonylurea derivatives

药物转运蛋白OATP1B3对CCK-8和磺酰脲衍生物胰腺作用影响的研究

基本信息

批准号：
222305952
负责人：
Privatdozentin Dr. Henriette Meyer zu Schwabedissen
金额：
--
依托单位：
Department für Biopharmazie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2012
资助国家：
德国
起止时间：
2011-12-31 至 2014-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/222305952?language=en
关键词：
Studies impact drug transporter OATP1B3

项目摘要

Transporters facilitating cellular uptake play a pivotal role in modulating the intracellular functions of their substrates. Organic Anion Transporting Polypeptides are one family of transporters mediating cellular uptake. Particularly, the members of the OATP1B-subfamily were focus of pharmacological studies as these proteins transport a variety of drugs in clinical use.In preparation of this proposal we were able to show expression of the uptake transporter OATP1B3 in the insulin-producing -islet cells of human pancreas. Considering that previous studies revealed choleystokinin-8 (CCK-8), an intestinal formed incretine as an OATP1B3-specific endogenous substrate and that our preliminary data and previous findings by others show interaction of several sulfonylurea derivatives with OATP1B3 the question of the physiological and pharmacological relevance of the pancreatic expression of OATP1B3 rises. In order to obtain insights in the function of OATP1B3 in -islet cells, a glucose-sensitive, insulin-producing, and OATP1B3-overexpressing cell-line will be generated and functionally characterized. The impact of the transporter on the cellular effects of CCK-8 and of sulfonylurea derivatives will be focus of the subsequent in vitro studies assessing the influence of the endogenous and exogenous substrates on the insulin secretion by transfected -islet cells. In addition, the potential interaction of sulfonylurea derivatives with the physiological function of CCK-8 will be determined. In addition to those cellular effects it will be aim to show direct transport of sulfonylurea derivatives by OATP1B3. Basis of a translational approach are our previous findings of function impairing, and frequently occurring genetic variants of OATP1B3. It is aim of the clinical study in healthy volunteers genotyped for OATP1B3 variants prior to study inclusion, to determine the influence of the respective polymorphisms on the physiological function of CCK-8. In order to do so, a two-armed study will be conducted. In the first treatment period the impact of the genetic variants on the systemic disposition of intestinal formed and secreted CCK-8 will be determined after intake of a standardized meal. It seems noteworthy, that OATP1B3 is highly expressed in hepatocytes and might therefore influence bioavailability of CCK-8. In the second treatment period the impact of genetic variants of OATP1B3 on the insulin release promoting effects of CCK-8 will be assessed after intake of 75 g Glucose. In addition to CCK-8, the levels of insulin and other known modulators of glucose homeostasis will be determined. The study has been approved by the local ethic committee and will be conducted in collaboration with the Department of Clinical Pharmacolgy of the Universitätsmedizin Greifswald.

促进细胞摄取的转运蛋白在调节其底物的细胞内功能中起关键作用。有机阴离子转运多肽是介导细胞摄取的转运蛋白家族之一。特别是OATP 1B亚家族的成员是药理学研究的焦点，因为这些蛋白质在临床上转运多种药物。在准备本提案时，我们能够显示摄取转运蛋白OATP 1B 3在人胰腺的胰岛素产生胰岛细胞中的表达。考虑到既往研究显示胆囊收缩素-8（CCK-8）（一种肠形成的肠促胰岛素）是OATP 1B 3特异性内源性底物，并且我们的初步数据和其他人的既往研究结果显示几种磺酰脲衍生物与OATP 1B 3相互作用，因此OATP 1B 3胰腺表达的生理学和药理学相关性问题增加。为了深入了解OATP 1B 3在胰岛细胞中的功能，将生成葡萄糖敏感、胰岛素产生和OATP 1B 3过表达的细胞系并进行功能表征。转运蛋白对CCK-8和磺酰脲衍生物的细胞效应的影响将是后续体外研究的焦点，这些研究评估了内源性和外源性底物对转染的胰岛细胞的胰岛素分泌的影响。此外，磺酰脲衍生物与CCK-8的生理功能的潜在相互作用将被确定。除这些细胞效应外，还旨在显示OATP 1B 3对磺酰脲衍生物的直接转运。翻译方法的基础是我们以前发现的功能损害和OATP 1B 3的频繁发生的遗传变异。本临床研究的目的是在纳入研究前对健康志愿者进行OATP 1B 3变体基因分型，以确定相应多态性对CCK-8生理功能的影响。为此，将进行双组研究。在第一个治疗阶段，将在摄入标准餐后确定遗传变异对肠道形成和分泌的CCK-8的全身分布的影响。值得注意的是，OATP 1B 3在肝细胞中高度表达，因此可能影响CCK-8的生物利用度。在第二个治疗阶段，将在摄入75 g葡萄糖后评估OATP 1B 3遗传变体对CCK-8促进胰岛素释放作用的影响。除CCK-8外，还将测定胰岛素和其他已知的葡萄糖稳态调节剂的水平。本研究已获得当地伦理委员会的批准，并将与Universitätsmedizin Greifswald的临床药理学系合作开展。