Correlation of CY3A5 genetic polymorphism with concentration/dosage of tacrolimus and individualized administration of tacrolimus after kidney transplantation

Junchang LIU

ABSTRACT

BACKGROUND:

Polymorphism of CYP3A5 gene can significantly affect the blood concentration of tacrolimus in the early period after kidney transplantation. Many studies in China are limited to the early 3 months after kidney transplantation with no concern on the long-term effect of tacrolimus in recipients.

OBJECTIVE:

To investigate the relationship between the polymorphism of CYP3A5 gene and tacrolimus concentration/dose (C0/D) in kidney transplant recipients, and to compare the differences among different genotypes, so as to provide an individualized drug regimen of tacrolimus after kidney transplantation.

METHODS:

Sixty-five adult recipients who underwent kidney transplantation and postoperative administration of tacrolimus (FK506) + mycophenolate mofetil (MMF) + prednisone (Pred) immunosuppressive therapy were divided into three groups according to their CYP3A5 genotypes detected preoperatively CYP3A5*1/*1, *1/*3, and *3/*3 groups. The whole blood concentration of tacrolimus was monitored in all the recipients, and C0/D value was recorded in each group at different time points after surgery. The study protocol was in line with the ethical requirements of Air Force Hospital of Northern Theater Command. RESULTS AND

CONCLUSION:

There were 6, 25 and 34 recipients of CYP3A5*1/*1, *1/*3 and *3/*3, respectively. The C0/D value of tacrolimus in the CYP3A5*1/*1 and *1/*3 groups was significantly lower than that in the CYP3A5*3/*3 group (P < 0.05). At 7 and 14 days after surgery, the C0/D value of tacrolimus in the CYP3A5*1/*1 group was lower than that in the CYP3A5*1/*3 group (P=0.028, P=0.034). In the CYP3A5*1/*1 group, the C0/D value of tacrolimus at 7 days after surgery was significantly lower than that at 6 months and 1 year after surgery (P=0.35, P=0.41). In the CYP3A5*1/*3 group, the C0/ D value of tacrolimus at 7 days after surgery was significantly lower than that at 3 months, 6 months and 1 year after surgery (P=0.029, P=0.07, P < 0.01), and that at 14 days and 1 month after surgery was significantly lower than that at 6 months and 1 year after surgery (P=0.04, P=0.39). In the CYP3A5*3/*3 group, the C0/D value of tacrolimus at 7 days after surgery was significantly lower than that at 3 months, 6 months and 1 year after surgery (P=0.029, P=0.03), and that at 14 days after surgery was significantly lower than that at 6 months and 1 year after surgery (P=0.022). Overall findings indicate that the polymorphism of CYP3A5 gene has a significant effect on the C0/D value of tacrolimus in kidney transplant recipients, which can be maintained for a long-term stable period after transplantation. For CYP3A5*1/*1 and *1/*3 recipients, the metabolism of tacrolimus is faster in the early stage, and the dosage of tacrolimus should be increased to maintain the target blood concentration, whereas for CYP3A5*1/*3 recipients, the dosage of tacrolimus may be moderately less than the former and the drug reduction rate should be slowed down in the later stage. CYP3A5*3/*3 recipients have a slow metabolism of tacrolimus, and should be given a small dose in the early stage, and the reduction rate should be accelerated in the later stage.