Role of a Novel Absorption Mechanism in Metformin Disposition and Pharmacology

新型吸收机制在二甲双胍处置和药理学中的作用

• 批准号: 8307412
• 负责人: DHIREN R THAKKER
• 金额: $ 31.39万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8307412
• 关键词: Address; Adverse effects; Apical; Attenuated; Back; Behavior; Biological Availability; Caco-2 Cells; Cations; Cell membrane; Cell model; Cells; Charge; Chemicals; Clinic; Diabetic mouse; Distal; Dose; Drug Kinetics; Drug Prescriptions; Enterocytes; Europe; Exhibits; Gastrointestinal Transit; Glucose; Goals; Health; Hepatic; Human; In Vitro; Incidence; Individual; Intestinal Absorption; Intestines; Investigation; Knowledge; Laboratories; Lactic Acidosis; Liver; Mannitol; Marketing; Mediating; Metformin; Modeling; Mus; Nature; Non-Insulin-Dependent Diabetes Mellitus; Oral; Orthologous Gene; Outcome; POU2F1 gene; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Actions; Pharmacology; Physiological; Play; Pre-Clinical Model; Prodrugs; Property; Relative (related person); Reporting; Research; Role; Route; Tablets; Testing; Therapeutic; Tissues; Travel; United States Food and Drug Administration; Work; absorption; adeno-associated viral vector; analog; apical membrane; base; basolateral membrane; db/db mouse; design; gastrointestinal; glucose uptake; improved; in vivo; inhibitor/antagonist; intestinal epithelium; monolayer; mouse model; novel; overexpression; response; small hairpin RNA; uptake

DESCRIPTION (provided by applicant): Metformin is the most widely prescribed drug for the treatment of Type II diabetes. It was approved for marketing by the U.S. Food and Drug Administration in 1994, yet the mechanisms involved in its intestinal absorption and its pharmacologic actions are not well understood to date. Despite its hydrophilic nature with net positive charge at physiological pH values, metformin exhibits high oral bioavailability (50-60%) with wide inter-subject variability. It is ineffective in 38% of patients, and can cause severe lactic acidosis in some. A major goal of the proposed research is to identify and characterize the intestinal transporter(s) and absorption mechanism of metformin, and elucidate their role in its pharmacologic actions. Recent observations in the PI's laboratory show that metformin is taken up across the apical cell membrane into Caco-2 cell monolayers, a well-established model for human intestinal epithelium, via the cation-selective tranaporters OCT1 and PMAT. Once inside the cell, metformin cannot egress across the basolateral membrane, resulting in intracellular accumulation during its absorptive transport. To understand the implications of these observations in the clinic, an experimental approach has been designed to achieve the following objectives: (i) Test if the mechanism of metformin transport observed in an in vitro static Caco-2 cell model applies to its transport behavior in the intestinal epithelium from mouse and humans. (ii) Elucidate the relationship between metformin transport mechanism in the mouse intestinal epithelium to its intestinal absorption, its pharmacologic profile, and adverse effects in a diabetic mouse model. (iii) Apply these results to retrospectively evaluate the highly variable oral bioavailability in humans, the lack of pharmacologic response to metformin in some, and the incidences of lactic acidosis in a small number of patients. . The proposed research addresses the gap in our knowledge regarding the pharmacokinetic and pharmacologic behavior of metformin. The results from the proposed work will improve understanding of the absorption mechanisms of other hydrophilic cationic drugs. The results will also provide a mechanistic basis for (i) inter- individual variability in therapeutic response to metformin and (ii) gastrointestinal side effects as well as lactic acidosis. Metformin analogs or prodrugs with improved therapeutic profile can be conceived based on the findings of this research PUBLIC HEALTH RELEVANCE: Metformin is a front-line therapy for type 2 diabetes, and yet much is unknown about its mechanism of oral absorption and its pharmacology. This project will attempt to identify the intestinal transporters that play pivotal role in the absorption of orally administered metformin. The research will also investigate the relative contribution of liver and intestine in the overall glucose-lowering effect of metformin. The results will provide a better understanding about the inter-patient variability in metformin's absorption and about the lack of response to metformin therapy in some patients.

描述（由申请人提供）：二甲双胍是治疗 II 型糖尿病最广泛的处方药物。它于1994年被美国食品和药物管理局批准上市，但迄今为止其肠道吸收机制及其药理作用尚不清楚。尽管二甲双胍在生理 pH 值下具有亲水性并带有净正电荷，但其口服生物利用度较高 (50-60%)，且受试者间差异较大。它对 38% 的患者无效，并且可能导致某些患者严重乳酸酸中毒。该研究的主要目标是鉴定和表征二甲双胍的肠道转运蛋白和吸收机制，并阐明它们在药理作用中的作用。 PI 实验室最近的观察表明，二甲双胍通过阳离子选择性转运蛋白 OCT1 和 PMAT 穿过顶端细胞膜进入 Caco-2 单层细胞（一种完善的人肠上皮模型）。一旦进入细胞内，二甲双胍就无法穿过基底外侧膜流出，导致其吸收运输过程中在细胞内积累。为了了解这些观察结果对临床的影响，设计了一种实验方法来实现以下目标：（i）测试在体外静态 Caco-2 细胞模型中观察到的二甲双胍转运机制是否适用于其在来自小鼠和人类的肠上皮。 (ii) 阐明二甲双胍在小鼠肠上皮中的转运机制与其肠道吸收、其药理学特征以及糖尿病小鼠模型中的不良反应之间的关系。 (iii) 应用这些结果来回顾性评估人类口服生物利用度的高度可变性、某些人对二甲双胍缺乏药理反应以及少数患者乳酸性酸中毒的发生率。 。拟议的研究填补了我们对二甲双胍药代动力学和药理学行为的知识空白。这项工作的结果将增进对其他亲水性阳离子药物吸收机制的理解。结果还将为（i）二甲双胍治疗反应的个体差异和（ii）胃肠道副作用以及乳酸性酸中毒提供机制基础。根据本研究的结果，可以设想具有改善治疗效果的二甲双胍类似物或前药 公众健康相关性：二甲双胍是 2 型糖尿病的一线治疗药物，但其口服吸收机制及其药理学尚不清楚。该项目将尝试确定在口服二甲双胍吸收中发挥关键作用的肠道转运蛋白。该研究还将调查肝脏和肠道在二甲双胍总体降糖作用中的相对贡献。这些结果将有助于更好地了解二甲双胍吸收的患者间差异以及某些患者对二甲双胍治疗缺乏反应的情况。