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ANALYSIS OF CYP 3A4 GENOTYPE VARIATION IN RENAL TRANSPLANT RECIPIENTS AND THE ASSOCIATION WITH CYCLOSPORIN CLEARANCE.
Sebron Harrison, B.S., William H. Barber, M.D., Larry S. McDaniel, Andrea Barker, B.S., Xinchun Zhou, M.D. and Olga D. McDaniel, Ph.D.. Jackson MS, USA, University of Mississippi Medical Center, 39216-4505, Surgery.
Most organ transplant recipients in addition to immunosuppressive drugs also take medications for other conditions. The adminstration of more than 2 drugs might have effect in drug distribution and excretion following long-term drug treatment. The CYP3A4 plays an important role in the metabolism of immunosuppressive drugs, including Cyclosporine. Because of variability in the drug uptake and clearance, this might have a great impact on the outcome of allograft survival. We have demonstrated interindividual variation in CYP 3A4 expression in different individuals. Such variations are due to the polymorphism within the promoter region of the genes, causing variation in the level of expression. The aim was to determine the allelic frequency of the CYP 3A4 variants in African-American patients and to examine a possible association with Cyclosporine elimination in the transplant settings. Blood samples from 77 patients and 67 matched controls were studied by single nucleotide polymorphism (SNP) and PCR. CYP3A4 G genotype was present in 82.5% of renal transplant patient population. There was no difference between G frequency in the patients as compared with control samples, but, GG genotype was 4-fold higher in patients than in controls. G was significantly higher in our study population (82.5%) as compared with African American population (53%) elsewhere. There was a trend towards higher Cyclosporine clearance index and AA variant, indicating that the effect of CYP3A4 might be more evident in a homozygous GG genotype. Such information might allow strategies for immunosuppressive drugs such as Cyclosporine and tacrolimus that are commonly used to prevent allograft rejections.