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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.

项目总结/摘要大多数实体器官接受者都使用他克莫司来预防排斥反应和维持移植物功能。的本研究的总体目标是评估大麻二酚（CBD）与他克莫司共同给药时的安全性。拟议的研究将全面定义大麻二酚，他克莫司， CYP3A5大麻二酚是CYP 3A 4和CYP 3A 5酶的有效抑制剂，CYP 3A 5是CYP 3A 4和CYP 3A 5的有效抑制剂。多态性酶在种群间的表达差异。在拟议的实验中，我们将揭示CBD的代谢是否受到CYP 3A 5的影响。基因型我们还将确定大麻二酚和大麻酚之间是否存在药物相互作用（DDI）。他克莫司，一种通过CYP 3A 4和CYP 3A 5代谢的免疫抑制剂。如果发现DDI，我们将确定该DDI是否在CYP 3A 5正常代谢者中更有效。我们假设CBD将引起药物间相互作用，需要在CYP 3A 5表达者中减少他克莫司剂量，非表达者。在目标1中，我们将在一系列PK研究中检验这一假设，研究对象是不同 CYP 3A 5基因型。主要结局是CYP 3A 5中他克莫司的曲线下面积（AUC）表达者和非表达者，同时以稳态浓度服用CBD。 CBD也可能导致与移植受体相关的药效学效应，独立于他克莫司浓度.因此，在目标2中，我们研究了CBD和他克莫司在治疗中的药效学相互作用。免疫系统我们将使用敏感的表型，如免疫细胞分布和细胞表达来源于单细胞测序的特征。在这些实验中收集的信息很重要，因为它预计这项工作将有助于医生建议他们的病人，包括移植受体，是否存在药物相互作用或服用大麻二酚是否安全。