Melding Pharmacogenomic Effect of MDR-1 and CYP3A5 Gene Polymorphism on Tacrolimus Dosing in Renal Transplant Recipients in Northern India

Abstract: Introduction Tacrolimus (TAC) is the mainstay immunosuppressant for renal transplantation. Narrow therapeutic index, multiple drug interactions and interindividual variability in pharmacokinetics enforce us for obligatory monitoring of therapeutic drug level. MDR-1 gene and CYP3A5 gene polymorphism may blend to achieve the optimum level. The optimum dose as per body weight is difficult to single out in the early post-transplant period. We aimed the study to analyze the melding effect of both gene polymorphism and elicit the dose depending on the combination of single nucleotide gene polymorphisms in northern Indian transplant recipients, where data is limited. Method The daily TAC dose, weight-adjusted doses (mg/kg/day), TAC trough blood concentration (average of at least 3 level), and dose-normalized with corresponding dose using TAC Co/weight-adjusted dose ratio (ng/ml/mg/kg/day) of 248 patients were recorded. All recipients were genotyped for the SNPs of CYP3A5 at intron 3 A6986G (the *3 or *1 allele), MDR1 at exons 12 (C1236T), 21 (G2677A/T) and 26 (C3435T). We analyzed the blending effect of mutant SNPs of MDR-gene and CYP3A5 for optimized TAC level. Result Amongst CYP3A5 genotypic variants, dose-adjusted TAC level was significantly lower, and the TAC dose required to achieve the target level was significantly higher in CYP3A5*1*1(expressor) than that of CYP3A5*1*3 and CYP3A5*3*3. Of the MDR-1 gene SNPs, only G2677T/A homozygous mutant was significantly associated with tacrolimus level and it was strongly correlated with P-gp expression.The daily TAC dose requirement was highest with a combination of CYP3A5*1*1 and homozygous mutant TT+AA genotype of G2677T/A and lowest with CYP3A5*3*3 and wild type GG of G2677T/A genotype. Conclusion Both CYP gene and MDR-1 gene polymorphism affect the TAC dose requirement and there is a need to look for both in an individual to achieve the target trough concentration.