SUN-113 COMBINATION OF *1/*1 WILD VARIANT OF CYP3A5 AND TT/AA MUTANT OF MDR G2677T/A GENE POLYMORPHISM REQUIRES HIGHER TACROLIMUS DOSE TO ACHIEVE TARGET TROUGH LEVEL

Abstract

Tacrolimus (Tac) is the most commonly used immunosuppressive drug in transplantation. Tac disposition has very narrow therapeutic range and great inter-individual variability in its pharmacokinetics. Achieving the target blood concentration is of crucial importance in the early stage after transplantation and to attain good transplant outcome. This differential bioavailability in trough Tac concentration may be due to expression of P-gp varying between individuals and/or differential metabolizing capacity of CYP450.Tac share CYP3A5 enzymes for their hepatic elimination and P-gp, a product of MDR-1 gene expressed on gut wall, renal tubular cells, hepatocytes, lymphocytes etc and works as transmembrane efflux pump which exports xenobiotics from inside the cell to outside. Hence we aimed this study to analyse the influence of the combination of MDR-1 and CYP3A5 SNPs on daily Tac requirement to achieve trough level post-transplantation. We recruited 248 renal transplant recipients (mean age 36.48±10.54; male (83.47%),all on Tac; MMF and prednisone in the study. Of the 248 patients; 110 had CGN; 65 had CIN; 7 had ADPKD; 21 had DKD; 8 had CKDu; 7 had DGGS; 3 had Alport's syndrome and 27 had other native kidney diseases. The mean creatinine level at the time of discharge was 1.15±0.27(0.48-2.31). P-gp expression was analyzed by flow cytometry and polymorphism was performed by PCR-RFLP. Of the 248; 123(49.59%) were CYP3A5*3/*3(non-expressers homozygous); 94(37.90%) CYP3A5*1/*3; and 31(12.5%) were CYP3A5*1/*1 (expressers). In MDR G2677T/A gene of 248 patients; 99(39.91%) were GG (wild type homozygous); 104(41.92%) were GT/GA (heterozygous) and 45(18.13%) were TT/AA (mutant homozygous) of MDR Gene. Tac trough concentration was high in *3/*3 as compare to *1*1(p=0.001) and *1*3 (p=0.022) respectively. CYP3A5*1/*1 patients had lower levels of dose-adjusted TAC (55.69±26.84 ng/mL/mg/kg/day) to achieve target blood level and required higher daily dose per weight (0.142±0.028mg/kg/day) than CYP3A5*1/*3 patients; 111.12±8.93ng/mL/mg/kg/day and 0.121±0.035mg/kg/day(p=0.022) and CYP3A5*3/*3 patients; 142.21±75.23ng/mL/mg/kg/day and 0.109±0.032mg/kg/day(p<0.001). Tac Co was low in TT/AA as compare to GG(p<0.001) and GT/GA(p<0.001) respectively and daily Tac dose requirement was high in TT/AA as compare to GG(p<0.001) and GT/GA(p=0.027) genotype to achieve target blood concentration of MDR G2677T/A gene. The P-gp expression was also high in TT/AA as compare to GG(p<0.001) and GT/GA(p<0.001). Genotype C1236T and C3435T of MDR-1 gene had no significant effect on Tac dose requirement. Patients having CYP3A5*1/*1(expresser) and TT/AA (homozygous mutant) of MDRG2677T/A genotype had highest Tac daily dose requirement (0.147mg/kg/day) and having CYP3A5*3/*3 (non-expresser) and GG of MDRG2677T/A (wild type) genotype requires lowest Tac dose (0.101 mg/kg/day) to achieve target Tac tough concentration (8-12ng/ml). Daily Tac dose requirement is highest in patients having CYP3A5 expresser and MDR G2677T/A homozygous mutant gene together. Genetic variants may predicts the optimal dose of Tac in renal transplant recipients.