Influence of combined CYP3A4 and CYP3A5 single-nucleotide polymorphisms on tacrolimus exposure in kidney transplant recipients

Tacrolimus (Tac), an immunosuppressant used for the prevention of graft rejection in kidney transplant patients, is characterized by a high interindividual variability of its pharmacokinetics. It is metabolized specifically by... [ view full abstract ]

Tacrolimus (Tac), an immunosuppressant used for the prevention of graft rejection in kidney transplant patients, is characterized by a high interindividual variability of its pharmacokinetics. It is metabolized specifically by the CYP3A isoenzyme: CYP3A4 and CYP3A5.The present study investigated in Tunisian renal transplant patients, the genetic polymorphisms of CYP3A4*1B -392A>G, CYP34*22 15389C>T and CYP3A5*3 6986A>G, and their influence on tacrolimus pharmacokinetics during early and late post-transplant (PT) phases

The present study investigated in Tunisian renal transplant patients, the genetic polymorphisms of CYP3A4*1B -392A>G, CYP34*22 15389C>T and CYP3A5*3 6986A>G, and their influence on tacrolimus pharmacokinetics during early and late post-transplant (PT) phases.

Methods

We included adult Tunisian patients having received Tac for de novo kidney grafts and undergone a therapeutic drug monitoring (TDM) of Tac by C₀ monitoring during early (1 to 90 days) and late (over 90 days) PT phases. The genomic DNA was extracted from peripheral blood mononuclear cells using a salting-out procedure. CYP3A4 and CYP3A5 genotyping was performed using 

polymerase chain reaction-restriction fragment length polymorphism (PCR–RFLP).

Results

Seventy-eight patients were enrolled in this study. During the early PT phase, only the CYP3A5*3 and the CYP3A4*22 polymorphisms correlate significantly with Tac dose-normalized C₀ (C₀/D ratio). During the late and all PT phases, only the CYP3A4*1B polymorphism correlates significantly with Tac C₀/D ratio. The mean daily doses (mg/kg) matching therapeutic C₀, regardless of the CYP3A genotypes were  0.68 ± 0.2 and 1.09± 0.17 , during early and late PT phase, respectively.

 Conclusions

Our data support a critical role of the CYP3A4*1B, CYP34*22 and CYP3A5*3 polymorphisms on the variation of Tac exposure during the early and the late PT phase, respectively. The establishment of customized Tac doses, according to CYP3A4/CYP3A5 genotype combination and the PT time, may allow preventing graft rejection and improving the safety profile of this drug.