A new functional CYP3A4 intron 6 polymorphism significantly affects tacrolimus pharmacokinetics in kidney transplant recipients.

BACKGROUND

Tacrolimus (Tac) is a potent immunosuppressant with considerable toxicity. Tac pharmacokinetics varies between individuals and thus complicates its use in preventing rejection after kidney transplantation. This variability might be caused by genetic polymorphisms in metabolizing enzymes.

METHODS

We used TaqMan analyses to evaluate the impact of a newly discovered CYP3A4 (cytochrome P450, family 3, subfamily A, polypeptide 4) single-nucleotide polymorphism (SNP) (rs35599367C>T; CYP3A4*22) on Tac pharmacokinetics in 185 renal transplant recipients who participated in an international randomized controlled clinical trial (fixed-dose, concentration-controlled study).

RESULTS

The overall mean daily-dose requirement to reach the same predose Tac blood concentration was 33% lower for carriers of the T variant allele than for rs35599367CC patients (95% CI, -46% to -20%; P = 0.018). When combined with the 3 genotype of the CYP3A5 (cytochrome P450, family 3, subfamily A, polypeptide 5) gene, the rs35599367C>T SNP was also associated with a risk of supratherapeutic Tac concentrations (>15 μg/L) during the first 3 days after surgery, with an odds ratio of 8.7 for carriers of the CYP3A4 T allele plus CYP3A53/3 (P = 0.027) and 4.2 for the CYP3A4 CC homozygotes plus CYP3A53/3 (P = 0.002), compared with CYP3A4 CC homozygotes having 1 or 2 CYP3A51 alleles. The overall increase in the Tac dose-adjusted trough blood concentration was +179% for carriers of the CYP3A4 T allele with CYP3A53/3 (P < 0.001), +101% for CYP3A4 CC homozygotes with CYP3A53/3 (P < 0.001), and +64% for CYP3A4 T allele carriers with CYP3A51 (P = 0.020),compared with CYP3A4 CC homozygotes with CYP3A51.

CONCLUSIONS

The CYP3A4 rs35599367C>T polymorphism is associated with a significantly altered Tac metabolism and therefore increases the risk of supratherapeutic Tac concentrations early after transplantation. Analysis of this CYP3A4*22 SNP may help in identifying patients at risk of Tac overexposure.