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.