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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：
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.

项目总结/文摘