Enteric and hepatic transporter mechanisms for pharmacokinetic natural product-drug interactions

药代动力学天然产物-药物相互作用的肠和肝转运机制

基本信息

批准号：
10226905
负责人：
John Daniel Clarke
金额：
$ 22.95万
依托单位：
WASHINGTON STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10226905
关键词：
Acute Address Allergic rhinitis Area Beverages Botanicals Budgets Caco-2 Cells Camellia sinensis Catechin Cell Line Cell membrane Chronic Clinical Consumption Data Diabetes Mellitus Disease Management Drug Exposure Drug Interactions Drug Kinetics Drug toxicity Electronic Mail Enteral Enterocytes Enzymes Gastrointestinal tract structure Glucuronides Goldenseal Green tea Hepatic Hepatocyte Herb Herbal supplement Human Immunosuppressive Agents In Vitro Kinetics Metformin Monitor Mycophenolic Acid Natural Product Drug Natural Products OATP Transporters Organ Transplantation Organic Cation Transporter Organic Cation Transporter 1 Pathway interactions Patients Pharmaceutical Preparations Plasma Positioning Attribute Property Raloxifene Research Risk Role System Testing Therapeutic Therapeutic Effect Therapeutic Index Time Toxic effect Transplant Recipients Ulcer base clinically translatable drug disposition drug efficacy in vivo interest monoamine mouse model overexpression preclinical study response serotonin transporter uptake

项目摘要

The Center of Excellence for Natural Product-Drug Interaction Research (NaPDI Center) was established to select, prioritize, and investigate 4-6 natural products with potential to perpetrate pharmacokinetic natural product-drug interactions (NPDIs). This effort was a massive undertaking that has been immensely successful. The green tea and goldenseal interactions described below were discovered by the NaPDI Center and several mechanisms were hypothesized and tested. Ultimately, due to time and budget constraints, the primary mechanisms were not definitively identified. NCCIH sent a specific request to further investigate the mechanisms of these interactions. This request provides us the unique opportunity to complete the mechanistic data for these important NPDIs. On September 27th, 2019 NCCIH sent an email highlighting two areas of interest pertaining to RFA-AT-20-001. The email stated, “Based on recent data on interactions involving green tea, NCCIH is interested in additional preclinical studies to better define the magnitude and significance of pharmacokinetic interactions of green tea and its major catechin constituents with mycophenolic acid.” The email continued, “Furthermore, there is emerging evidence that components of the botanical goldenseal have potentially significant interactions with metformin. Thus, we are also interested in further preclinical studies to clarify the mechanisms associated with observed pharmacokinetic interactions between goldenseal and metformin.” This application will address two hypotheses organized into two specific aims: Aim 1: Determine the magnitude and significance of pharmacokinetic interactions of green tea with mycophenolic acid. Hypothesis- Enteric and hepatic organic anion transporting polypeptide (OATP) uptake transporters are responsible for the green tea- induced decrease in raloxifene and mycophenolic acid systemic exposure. Aim 2: Clarify the mechanisms associated with observed pharmacokinetic interactions between goldenseal and metformin. Hypothesis- Enteric organic cation transporter (OCT)3 is predominantly responsible for the goldenseal-induced decrease in metformin systemic exposure. Each aim is divided into two studies: Studies 1.1 and 2.1 will determine the in vitro transporter kinetics of the NPDIs in overexpression systems and in Caco-2 or hepatocyte systems; Studies 1.2 and 2.2 will determine the in vivo magnitude and significance of the NPDIs in clinically translatable murine models. Completion of this research will impact prescribing practices for metformin and mycophenolic acid and may be extended to other drugs that are substrates for these enteric and hepatic transporters.

天然产物-药物相互作用研究卓越中心（NaPDI中心）的成立是为了选择、优先排序并研究 4-6 种有潜力发挥药代动力学天然作用的天然产物产品-药物相互作用（NPDI）是一项艰巨的任务，并且取得了巨大成功。下面描述的绿茶和白毛茛相互作用是由 NaPDI 中心和几个研究人员发现的最终，由于时间和预算的限制，主要机制得到了资本化和测试。 NCCIH 发出了进一步调查该机制的具体请求。该请求为我们提供了完成这些相互作用的机械数据的独特机会。重要的 NPDI。 2019 年 9 月 27 日，NCCIH 发送了一封电子邮件，强调了与 RFA-AT-20-001 相关的两个感兴趣领域。该电子邮件称：“根据最近有关绿茶相互作用的数据，NCCIH 有兴趣参与更多临床前研究，以更好地确定绿茶药代动力学相互作用的程度和意义其主要儿茶素成分为霉酚酸。”电子邮件继续说道，“此外，还有新出现的证据表明，金印草的成分与以下物质具有潜在的显着相互作用：因此，我们也有兴趣进行进一步的临床前研究，以阐明与二甲双胍相关的机制。观察到金印草和二甲双胍之间的药代动力学相互作用。” 该应用程序将解决两个假设，这两个假设分为两个具体目标：目标 1：确定大小绿茶与麦考酚酸的药代动力学相互作用的假设-肠和意义。肝脏有机阴离子转运多肽（OATP）摄取转运蛋白负责绿茶- 诱导雷洛昔芬和麦考酚酸全身暴露量减少目标 2：阐明机制。与观察到的金毛草和二甲双胍之间的药代动力学相互作用相关。有机阳离子转运蛋白 (OCT)3 是金印草引起的每个目标分为两项研究：研究 1.1 和 2.1 将确定体外试验。 NPDI 在过表达系统和 Caco-2 或肝细胞系统中的转运动力学研究 1.2； 2.2 将确定临床可转化小鼠体内 NPDI 的大小和意义这项研究的完成将影响二甲双胍和霉酚酸的处方实践。可以扩展到作为这些肠和肝转运蛋白底物的其他药物。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Hepatic organic anion transporting polypeptides mediate disposition of milk thistle flavonolignans and pharmacokinetic silymarin-drug interactions.

肝脏有机阴离子转运多肽介导水飞蓟黄酮木脂素的处置和药代动力学水飞蓟素-药物相互作用。

DOI：
发表时间：
2021-06
期刊：
影响因子：
0
作者：
Lynch, Katherine D;Montonye, Michelle L;Tian, Dan;Arman, Tarana;Oyanna, Victoria O;Bechtold, Baron J;Graf, Tyler N;Oberlies, Nicholas H;Paine, Mary F;Clarke, John D
通讯作者：
Clarke, John D

Goldenseal-Mediated Inhibition of Intestinal Uptake Transporters Decreases Metformin Systemic Exposure in Mice.

金印介导的肠道摄取转运蛋白抑制可减少小鼠二甲双胍的全身暴露。

DOI：
发表时间：
2023-11
期刊：
影响因子：
0
作者：
Oyanna, Victoria O;Garcia;Bechtold, Baron J;Lynch, Katherine D;Call, M Ridge;Horváth, Miklós;Manwill, Preston K;Graf, Tyler N;Cech, Nadja B;Oberlies, Nicholas H;Paine, Mary F;Clarke, John D
通讯作者：
Clarke, John D

Multi-factorial pharmacokinetic interactions: unraveling complexities in precision drug therapy.

多因素药代动力学相互作用：揭示精准药物治疗的复杂性。