#3185 Influence of Combined Cyp 3a4/5 and Por*28 Genetic Polymorphisms on Tacrolimus and Cclosporine Dose Requirements in Incident Renal Transplant Patients

Abstract

Background and Aims Calcineurin inhibitors, cyclosporine and tacrolimus have a narrow therapeutic index and have wide intra- and inter individual pharmacokinetic variability. They are metabolized mainly by CYP3A4 and CYP3A5. The P450 oxidoreductase POR*28 variant allele has been associated with changes in cytochrome P450 enzymatic activity that can affect the therapeutic level of both medications. The aim of this study is to investigate the allelic frequency of the POR*28 in Egyptian renal transplant patients and to evaluate the effect of the presence of CYP3A5*1, CYP3A4*22, and POR*28 genetic polymorphism on calcineurins inhibitos dose requirements and adjustments. Method A prospective clinical trial that included 130 renal transplant patients placed on either tacrolimus or cyclosporine. Patients were genotyped for POR*28, CYP3A4*22, and CYP3A5*1. The relation between the present genetic polymorphisms and tacrolimus and cyclosporine doses and dose adjustments were studied at days 14, 30, and 90 post-transplantation. Results The POR*28 allele frequency in the studied population was 29.61%. The tacrolimus dose-adjusted trough concentration ratio (C0/D) was highly statistically significant in the fast metabolizers group (CYP3A5*1/POR*28T carriers) than in the slow metabolizers group (CYP3A5*3/*3/CYP3A4*22 carriers) throughout the study (14, 30, and 90 days) (p value 0.001, <0.001, and 0.003, respectively). There was no significant effect for this gene combination on cyclosporine (C0/D). Conclusion Combining the CYP3A5*1, POR*28, and CYP3A4*22 genotypes can be of significant value in early tacrolimus dose requirements and adjustments. However, it does not have any influence on cyclosporine dose requirements.