Long-Term Influence of CYP3A5, CYP3A4, ABCB1, and NR1I2 Polymorphisms on Tacrolimus Concentration in Chinese Renal Transplant Recipients.

ABSTRACT

BACKGROUND: The highly pharmacokinetic variability of tacrolimus makes it difficult to adjust the dose. In the current study, we investigated the influence of gene polymorphisms and other clinical factors on long-term tacrolimus dosing in Chinese renal transplant recipients. METHODS: A total of 276 renal transplant recipients were enrolled. The tacrolimus trough concentration and other clinical variables were recorded for 5 years following transplantation. Eight single nucleotide polymorphisms in four genes (CYP3A5, CYP3A4, ABCB1, and NR1I2) were genotyped using polymerase chain reaction-restriction fragment length polymorphism analysis and sequencing. The dose-adjusted tacrolimus trough concentrations were calculated and compared among patients according to allelic status. RESULTS: The alleles CYP3A5*3 and CYP3A4*18B were significantly associated with dose-adjusted tacrolimus blood trough concentrations and had a strong time-genotype interaction with tacrolimus pharmacokinetics. NR1I2 g.7635A>G had a significant interaction with time, but the dose-adjusted tacrolimus concentration did not significantly differ over 5 years posttransplantation, except for the GG genotype of NR1I2 g.7635A>G. Sex differences had an important influence on tacrolimus concentration during the later post-transplantation period. CONCLUSIONS: The interindividual variability of tacrolimus concentration appears to be due in part to the effects of these identified genetic variants and clinical characteristics. Thus, genotyping of the CYP3A4 and CYP3A5 genes should be considered with respect to determining tacrolimus dose regimens during the post-transplantation period.