Drug-gene-nutraceutical interactions of cannabidiol

项目摘要/摘要 大多数实体器官接受者都开了他克莫司，以防止排斥反应和维持同种异体移植的功能。这个 这项研究的总体目标是评估大麻二醇(CBD)与他克莫司联合应用时的安全性。 拟议的研究将全面定义大麻二醇、他克莫司、 和细胞色素P3A5。大麻二酚是一种有效的CYP3A4和CYP3A5酶的抑制剂，而CYP3A5是一种 具有不同种群间表达差异的多态酶。 在拟议的实验中，我们将揭示细胞色素P3A5是否影响CBD的新陈代谢 基因分型。我们还将确定大麻二酚和大麻之间是否存在药物-药物相互作用(DDI)。 他克莫司，一种由细胞色素P3A4和细胞色素P3A5代谢的免疫抑制剂。如果确认了DDI，我们将 确定这种DDI在CYP3A5正常代谢物中是否更有效。我们假设CBD将 引起药物-药物相互作用，需要他克莫司在CYP3A5表达细胞中的剂量比 非表现者。在目标1中，我们将在一系列PK研究中验证这一假设，研究对象为不同性别的人 CYP3A5基因分型。主要结果是CYP3A5中他克莫司的曲线下面积(AUC) 在稳定浓度下服用CBD时，表达和非表达。 CBD也可能导致与移植受者相关的药效学效应，而不依赖于他克莫司 集中精神。因此，在目标2中，我们研究了CBD和他克莫司在体内的药效学相互作用。 免疫系统。我们将使用免疫细胞分布和细胞表达等敏感表型 从单细胞测序中获得的签名。在这些实验中收集的信息很重要，因为它 预计这项工作将帮助医生建议他们的患者，包括移植接受者，是否 是否存在药物相互作用或服用大麻二醇是否安全。

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.