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Principal Investigator: Michael Thomas Eadon
Organization: INDIANA UNIVERSITY INDIANAPOLIS
Fiscal Year: 2024
Award: $631,061
Funding agency: National Center for Complementary and Integrative Health
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.
Terms: <Address><Affect><African American group><African American individual><African American people><African American population><African Americans><Agriculture><Allografting><American><Animal Model><Animal Models and Related Studies><Area Under Curve><Asian><Assay><Bioassay><Biological Assay><CP34><CYP3><CYP3A><CYP3A4><CYP3A4 gene><CYP3A5><CYP3A5 gene><Cannabidiol><Cannabis><Case Study><Cell Body><Cells><Chronic Kidney Failure><Chronic Renal Disease><Chronic Renal Failure><Clinical><Clinical Trials><Complement><Complement Proteins><Cross-Over Studies><Crossover Studies><Cytochrome P450 3A4><Cytochrome P450, Subfamily IIIA, Polypeptide 4><Cytochrome P450, Subfamily IIIA, Polypeptide 5><Cytochrome P450PCN1><Data><Dose><Drug Interactions><Drug Kinetics><Drug Metabolism Inhibition><Drugs><Enzyme Gene><Enzymes><Epidiolex><Epilepsy><Epileptic Seizures><Epileptics><Ethics><European><Exclusion><Explosion><Exposure to><Expression Signature><FAMILY III P450><FDA approved><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Gene Expression Profile><Genes><Genotype><Glean><Glucocorticoid-Inducible P450><Goals><Health><Hepatic><Human><Immune><Immune system><Immunes><Immunochemical Immunologic><Immunologic><Immunological><Immunologically><Immunologics><Immunology><Immunosuppressants><Immunosuppression><Immunosuppression Effect><Immunosuppressive Agents><Immunosuppressive Effect><Immunosuppressive drug><Immunosuppressive treatment><In Vitro><Individual><Intermediary Metabolism><Investigation><Ketoconazole><Learning><Liver Microsomes><Lymphatic cell><Lymphocyte><Lymphocyte Subtypings><Lymphocytic><Mediator><Medication><Metabolic Processes><Metabolism><Modern Man><Nifedipine Oxidase><Nutraceutical><Oils><Organ><Outcome><P450C3><P450PCN1><P450PCN3><PK/PD><Patients><Pharmaceutical Preparations><Pharmacodynamics><Pharmacogenomics><Pharmacokinetics><Phenotype><Population><Race><Races><Regulatory T-Lymphocyte><Renal function><Research><Risk><Seizure Disorder><Series><Short interfering RNA><Single cell seq><Small Interfering RNA><Solid><Steroid-Inducible P450- III><Study models><Tacrolimus><Testing><Toxic effect><Toxicities><Transplant Recipients><Transplantation><Treg><United States><Vulnerable Populations><Work><case report><chronic kidney disease><chronic pain control><chronic pain intervention><chronic pain management><chronic pain therapy><chronic pain treatment><clinical relevance><clinically relevant><complementation><drug/agent><epilepsia><epileptogenic><ethical><experiment><experimental research><experimental study><experiments><flow cytophotometry><gene expression pattern><gene expression signature><high risk group><high risk individual><high risk people><high risk population><immune suppression><immune suppressive activity><immune suppressive agent><immune suppressive function><immune suppressor><immunosuppressed><immunosuppressive activity><immunosuppressive function><immunosuppressive response><immunosuppressive substance><immunosuppressor><improved><infection risk><inhibitor><interest><kidney function><knock-down><knockdown><lymph cell><model of animal><nutrition><organ transplant patient><organ transplant recipient><pharmacokinetics and pharmacodynamics><pill><prevent><preventing><primary outcome><racial><racial background><racial origin><regulatory T-cells><safety assessment><siRNA><single cell next generation sequencing><single cell sequencing><success><transcriptional profile><transcriptional signature><transplant><transplant patient><treat chronic pain><volunteer><vulnerable group><vulnerable individual><vulnerable people>