Influence of combined CYP3A4 and CYP3A5 single-nucleotide polymorphisms on tacrolimus exposure in kidney transplant recipients: a study according to the post-transplant phase

Aim: The present study investigated in Tunisian renal transplant patients, genetic polymorphisms of CYP3A4 -392A> G and CYP3A5 6986A> G and their influence on tacrolimus (Tac) pharmacokinetics during early and late post-transplant (PT) phases and established customized ranges of Tac doses matching the C-0 target levels according to CYP3A4 and CYP3A5 genotype combination and the PT phase. Patients & methods: We included adult Tunisian patients having received Tac for de novo kidney grafts and undergone a therapeutic drug monitoring of Tac by morning C-0 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 promoter (rs2740574; -392A> G) and CYP3A5 (rs776746; 6986A> G) SNP genotyping was analyzed using PCR-RFLP. Results: Fifty-two patients were enrolled in the study. During the early PT phase, the CYP3A5 polymorphism but not that of CYP3A4, correlates significantly with Tac dose-normalized C-0 (C-0/D ratio). During the late PT phase, the effect of CYP3A4 polymorphism becomes significant and that of CYP3A5 becomes nonsignificant on Tac C-0/D Tac. The mean daily doses (mg/kg) matching therapeutic C-0, regardless of the CYP3A genotypes, were 0.16 +/- 0.05 and 0.10 +/- 0.05 during early and late PT phase, respectively. Carriers of the CYP3A4* 1B allele require higher doses to maintain the C-0 in the therapeutic range during the two PT phases. However, patients carrying the CYP3A5* 1 require significant higher Tac doses, only during the early phase. Conclusion: Our data support a critical role of the CYP3A5 6986A> G and CYP3A4 -392A> G 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. Further studies are needed to investigate this issue.