Pharmacogenomics of ADRs: Calcineurin Inhibitor Toxicity

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DESCRIPTION (provided by applicant): The overall objective of this grant proposal is to identify genetic and demographic traits that affect the risk of calcineurin-induced renal dysfunction in liver transplantation patients. Calcineurin inhibitors (CNIs), cyclosporine and tacrolimus, are mainstay immunosuppressive drugs used to prevent graft rejection, but at therapeutic blood concentrations, they can cause irreversible damage to the kidney in approximately 30-40% of patients. The risk of CNI renal dysfunction appears to be greater for females than males. With the following specific aims, we will test the hypothesis that individual risk for post-transplantation renal dysfunction is determined in significant part by inherited mutations in genes (MDR1 and CYP3AS) that control the efflux or metabolism of CNIs in renal tubular epithelial cells, and by patient gender: Aim 1. Conduct a prospective study to determine whether the progression of renal dysfunction in liver transplantation patients differs as a function of MDR1 and CYP3A5 genotypes and patient gender. Aim 2. Demonstrate that expression of the MDR1 T2677 and CYP3AS*I genes enhance cellular efflux/metabolism of CNIs and reduce cytotoxicity in transfected renal epithelial cells, and that the MDR1 T2677 and CYP3A5*I gene products are more active than respective MDRI G2677 and CYP3A5*3 gene products. Aim 3. Demonstrate that the renal clearance of CNIs and renal production and clearance of primary CNI metabolites is enhanced for individuals with the MDR1 TT2677 and CYP3A5*I/*3 genotypes, respectively. We will also test the hypothesis that the MDR1 mutations that affect renal dysfunction following CNI use, also influence the uptake of CNIs into T-lymphocyte cell populations that mediate graft rejection, and potentially affect the risk of acute graft rejection. This will be tested with the following Specific Aim: Aim 4. Determine whether common MDR1 mutations affect the efflux kinetics of Rhl23 and the CNIs in CD4+ and CD8+ T-lymphocytes from healthy volunteers and liver transplantation patients. If we can identify genetic and demographic risk factors for CNI-induced renal dysfunction in the transplantation population, this may permit the implementation of cost-effective, prospective genotyping to aid in individualizing immunosuppressive therapy.