Influence of CYP3A polymorphisms on tacrolimus pharmacokinetics in kidney transplant recipients.

Tacrolimus is characterized by a highly variable pharmacokinetics (PK) and a small therapeutic window. It is metabolized specifically by the CYP3A isoenzymes. This study aimed to determine, in kidney transplant patients, the influence of different genotypic clusters involving these SNPs CYP3A4*1B, CYP3A4*22, and CYP3A5*3 on Tacrolimus bioavailability during the first (PTP1) and the second (PTP2) posttransplant phase (PT). We included kidney transplant patients who received Tacrolimus and underwent drug monitoring by C0 monitoring. CYP3A4 and CYP3A5 genotyping were performed using PCR-RFLP. We classified the patients into four groups: Slow, Intermediate, rapid, and ultra-rapid metabolizers. We included 80 patients. The Tacrolimus dose-normalized C0 (C0/D ratio) was significantly decreased in intermediate, rapid, and ultra-rapid comparing with slow metabolisers. During PTP1 only CYP3A5*3 and CYP3A4*22 polymorphisms correlate significantly with C0/D ratio. Regardless of the PT phase and during the late one, only the CYP3A4 polymorphisms correlate significantly with the C0/D ratio. We identified that these SNPs are all associated independently with Tacrolimus exposure in different PT phases. Moreover, we are the first to define a genotypic cluster including the three CYP3A SNPs.

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 C0 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 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 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 C0 (C0/D ratio). During the late PT phase, the effect of CYP3A4 polymorphism becomes significant and that of CYP3A5 becomes nonsignificant on Tac C0/D Tac. The mean daily doses (mg/kg) matching therapeutic C0, 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 C0 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.