The Effect Of CYP3A5 And MDR-1 Polymorphisms On The Metabolism Of Tacrolimus In Renal Transplantation Recipient

Objective:This study was to detect CYP3A5*3, MDR1 C1236T and C3435T polymorphisms of renal transplantation recipients by pyrosequencing assay and to investigate the impact of CYP3A5*3, MDR1 C1236T and C3435T polymorphisms on tacrolimus(FK506) pharmacokinetics in living renal transplant recipients, to approach the significance of detecting CYP3A5*3, MDR1 C1236T and C3435T polymorphism in renal recipients that take FK506 as basic immunosuppressant, and to provide a fundament for individualized FK506 therapy in renal transplantation recipients based on gene polymorphisms.Methods:Eighty-six renal recipients receiving FK506 as basic immunosuppressant were genotyped for CYP3A5*3 polymorphism by the pyrosequencing assays. FK506 trough concentration of the patients was measured by enzyme multiplied immunoassay technique, the clinical date within six months post-transplantation were collected and the FK506 concentration/adjust dose ratio were compared among the 3 subgroups within the CYP3A5*3, MDR1 C1236T and C3435Tgroups.Result:Significant correlation was found between the CYP3A5*3 polymorphism and FK506 pharmacokinetics. The FK506 concentration /adjusted dose ratio of CYP3A5*1/*1 and *1/*3 patients were significantly lower than those of *3/*3 patients at the same time during the first six months post-transplantation (P<0.05), no significant difference was found in the FK506 concentration/adjusted dose ratio between CYP3A5*1/*1 and *1/*3 patients. No correlation was found between MDR1 C1236T polymorphism and the FK506 concentration/adjusted dose ratio in living related renal transplant patients. MDR1 C3435T polymorphism had some effect on the pharmacokinetics of FK506. Patients who were homozygous for the MDR1 3435 CC showed significantly lower FK506 concentration/dose-adjusted ratio compared with subjects of 3435 TT and CT genotypes (P<0.05), the ratio was no difference between the 3435 CT and TT patients. But the effect of MDR1 C3435T polymorphism on the pharmacokinetics of FK506 was not significant anymore when patients were subclassified as CYP3A5 expressors (CYP3A5*1 carriers) and nonexpressors (CYP3A5*3/*3).Conclusion:Both CYP3A5*3 and MDR1 C3435T polymorphisms has some effect on FK506 pharmacokinetics, but the effect of CYP3A5*3 is more powerful. Evaluating the CYP3A5*3 polymorphism, rather than MDR1 polymorphisms, of the recipients prior to transplantation by the pyrosequencing assay may be helpful in determining an appropriate initial dosage, rapidly achieving adequate immunosuppression, and ultimately improving the outcome of renal transplantation.