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：
10366842
负责人：
Michael Thomas Eadon
金额：
$ 66.01万
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/10366842
关键词：
Address Affect African American population Agriculture Allografting American Animals 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 Enzymes Epidiolex Epilepsy Ethics European Exposure to FDA approved Flow Cytometry Gene Expression Profile Genes Genotype Glean Goals Health Hepatic Human Immune Immune system Immunologics Immunosuppression Immunosuppressive Agents In Vitro Individual Investigation Ketoconazole Lead Liver Microsomes Lymphocyte Mediator of activation protein Metabolism Nutraceutical Oils Organ Outcome Patients Pharmaceutical Preparations Pharmacodynamics Pharmacogenomics Phenotype Population Race Regulatory T-Lymphocyte Renal function Research Risk Safety Series Small Interfering RNA Solid Study models Tacrolimus Testing Toxic effect Transplant Recipients Transplantation Immunology United States Ursidae Family Vulnerable Populations Work base chronic pain clinically relevant drug metabolism experimental study high risk population immunosuppressed improved inhibitor interest knock-down nutrition organ transplant recipient pharmacokinetics and pharmacodynamics pill prevent primary outcome 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.

项目概要/摘要大多数实体器官接受者都会服用他克莫司来预防排斥反应并维持同种异体移植功能。这本研究的总体目标是评估大麻二酚 (CBD) 与他克莫司联合用药时的安全性。拟议的研究将全面定义大麻二酚、他克莫司、和 CYP3A5。大麻二酚是 CYP3A4 和 CYP3A5 酶的有效抑制剂，CYP3A5 是一种跨群体表达差异的多态性酶。在拟议的实验中，我们将揭示 CBD 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大麻二酚之间是否存在药物相互作用（DDI）他克莫司，一种由 CYP3A4 和 CYP3A5 代谢的免疫抑制剂。如果发现 DDI，我们将确定该 DDI 在 CYP3A5 正常代谢者中是否更有效。我们假设 CBD 将引起药物间相互作用，需要比 CYP3A5 表达者更大程度地减少他克莫司剂量非表达者。在目标 1 中，我们将在一系列不同个体的 PK 研究中检验这一假设。 CYP3A5 基因型。主要结果是 CYP3A5 中的他克莫司曲线下面积 (AUC) 以稳态浓度服用 CBD 时，表达者和非表达者。 CBD 还可能导致与移植受者相关的药效学效应，独立于他克莫司专注。因此，在目标 2 中，我们研究了 CBD 和他克莫司在免疫系统。我们将使用敏感表型，例如免疫细胞分布和细胞表达来自单细胞测序的特征。在这些实验中收集的信息很重要，因为预计这项工作将帮助从业者向他们的患者（包括移植受者）提供建议：是否存在药物相互作用或服用大麻二酚是否安全。