Drug-gene-nutraceutical interactions of cannabidiol

大麻二酚的药物-基因-营养药物相互作用

基本信息

批准号：
10577835
负责人：
Michael Thomas Eadon
金额：
$ 65.34万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-22 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10577835
关键词：
Address Affect African American population Agriculture Allografting American Animal Model Area Under Curve Asian Biological Assay CYP3A4 gene CYP3A5 gene Cannabidiol Cannabis Case Study Cells Chronic Kidney Failure Clinical Clinical Trials Complement Cross-Over Studies Data Dose Drug Interactions Drug Kinetics Drug Metabolism Inhibition Enzymes Epidiolex Epilepsy Ethics European Exclusion Explosion Exposure to FDA approved Flow Cytometry Gene Expression Profile Genes Genotype Glean Goals Health Hepatic Human Immune Immune system Immunologics Immunology Immunosuppression Immunosuppressive Agents In Vitro Individual Investigation Ketoconazole Learning Liver Microsomes Lymphocyte Lymphocyte Subtypings Mediator Metabolism Nutraceutical Oils Organ Outcome Patients Pharmaceutical Preparations Pharmacodynamics Pharmacogenomics Phenotype Population Race Regulatory T-Lymphocyte Renal function Research Risk Series Small Interfering RNA Solid Study models Tacrolimus Testing Toxic effect Transplant Recipients Transplantation United States Vulnerable Populations Work chronic pain management clinically relevant experimental study high risk population immunosuppressed improved infection risk inhibitor interest knock-down nutrition organ transplant recipient pharmacokinetics and pharmacodynamics pill prevent primary outcome safety assessment single cell sequencing success volunteer

项目摘要

Project Summary/Abstract Most solid organ recipients are prescribed tacrolimus to prevent rejection and maintain allograft function. The overall goal of this study is to assess the safety of cannabidiol (CBD) when co-administered with tacrolimus. The proposed studies will comprehensively define the pharmacokinetic interactions of cannabidiol, tacrolimus, and CYP3A5. Cannabidiol is a potent inhibitor of the CYP3A4 and CYP3A5 enzymes and CYP3A5 is a polymorphic enzyme with expression differences across populations. During the proposed experimentation, we will uncover whether the metabolism of CBD is affected by CYP3A5 genotype. We will also determine whether a drug-drug interaction (DDI) exists between cannabidiol and tacrolimus, an immunosuppressant metabolized by CYP3A4 and CYP3A5. If a DDI is identified, we will determine whether this DDI is more potent in CYP3A5 normal metabolizers. We hypothesize that CBD will cause a drug-drug interaction requiring a much larger dose reduction of tacrolimus in CYP3A5 expressors than non-expressors. In aim 1, we will test this hypothesis in a series of PK studies in individuals with different CYP3A5 genotypes. The primary outcome is the tacrolimus area-under-the-curve (AUC) in CYP3A5 expressors and non-expressors while taking CBD at a steady state concentration. CBD may also lead to pharmacodynamic effects relevant to transplant recipients, independent of tacrolimus concentration. Thus, in aim 2, we investigate the pharmacodynamic interactions of CBD and tacrolimus in the immune system. We will use sensitive phenotypes such as immune cell distribution and cell expression signatures derived from single cell sequencing. The information gleaned in these experiments is important as it is expected that this work will help practitioners advise their patients, including transplant recipients, whether drug interactions are present or whether it is safe to take cannabidiol.

项目摘要/摘要大多数固体器官接受者是他克莫司的开具，以防止排斥和维持同种异体移植功能。这这项研究的总体目标是评估与克莫司共同管理大麻二醇（CBD）的安全性。拟议的研究将全面定义大麻二酚，他克莫司，他的药代动力学相互作用和CYP3A5。大麻二酚是CYP3A4和CYP3A5酶的有效抑制剂，CYP3A5是一个多态酶在人群之间具有表达差异。在提出的实验中，我们将发现CYP3A5的代谢是否受到CYP3A5的影响基因型。我们还将确定大麻二酚和克莫司，一种由CYP3A4和CYP3A5代谢的免疫抑制剂。如果确定了DDI，我们将确定该DDI是否在CYP3A5正常代谢器中更有效。我们假设CBD将引起药物相互作用，需要降低他克莫司的剂量比非表达者。在AIM 1中，我们将在一系列PK研究中检验该假设 CYP3A5基因型。主要结果是CYP3A5中的克莫司曲曲霉（AUC）表达式和非表达器以稳态浓度服用CBD。 CBD还可能导致与移植受者有关的药效学作用，而与克莫司无关专注。因此，在AIM 2中，我们研究了CBD和他克莫司的药效学相互作用免疫系统。我们将使用敏感的表型，例如免疫细胞分布和细胞表达源自单细胞测序的特征。这些实验中收集的信息很重要，因为期望这项工作将帮助从业者建议患者，包括移植接受者，无论是否存在药物相互作用，或者是否可以安全服用大麻二酚。