Impact of the CYP3A4*1G polymorphism and its combination with CYP3A5 genotypes on tacrolimus pharmacokinetics in renal transplant patients.

AIM

Tacrolimus is a substrate of CYP3A4 and CYP3A5. The present study investigated the impact of the CYP3A41/1G polymorphism compared with CYP3A5 genotypes on the dose-adjusted pharmacokinetics of tacrolimus. The effects of the polymorphism on the variability in tacrolimus pharmacokinetics among patients with the CYP3A51 allele (CYP3A5 expresser) and among those with CYP3A53/*3 genotype (nonexpresser) were also studied.

MATERIALS & METHODS: A total of 136 renal allograft recipients were given repeated doses of tacrolimus every 12 h. On day 28 after the renal transplantation, blood tacrolimus concentrations were measured, and dose-adjusted pharmacokinetics were determined and compared with the corresponding genotype.

RESULTS

The dose-adjusted AUC₀₋₁₂ and C₀ of tacrolimus were significantly lower in patients with the CYP3A41G allele and CYP3A5 expressers than those with the CYP3A41/1 genotype and nonexpressers, respectively. In a multiple regression analysis, the dose-adjusted AUC₀₋₁₂ and C₀ values were associated with CYP3A41/1 (p = 0.018 and 0.040, respectively) and CYP3A53/3 (p < 0.001 each). The standardized regression coefficient for the AUC₀₋₁₂ of tacrolimus was approximately twofold less for CYP3A41/1 than CYP3A53/3. The lowest dose-adjusted AUC₀₋₁₂ was found in CYP3A5 expressers with the CYP3A41G allele.

CONCLUSION

The CYP3A4*1/1G polymorphism was associated with the pharmacokinetics of tacrolimus, however, its contribution to dose-adjusted pharmacokinetics was approximately twofold less than that of the CYP3A51/3 polymorphism. Although its effect on CYP3A4 activity is not clear, CYP3A41/*1G may be a candidate for a polymorphism affecting the interindividual variability in tacrolimus pharmacokinetics among CYP3A5 expressers.