Pharmacogenetics of tacrolimus after renal transplantation: analysis of polymorphisms in genes encoding 16 drug metabolizing enzymes

Abstract

BACKGROUND: Tacrolimus (Tac) is an immunosuppressive drug used to prevent post-transplant (PT) organ rejection. Continuous Tac monitoring is necessary to adjust the dose and prevent toxicity or rejection. Tac is metabolized by cytochrome-P450 (CYP) enzymes, and variation at the CYP and other drug metabolizing enzymes could influence Tac bio-availability and dose requirements. Our aim was to define the effect of DNA variants at 16 drug metabolising enzymes on Tac dose in patients with kidney transplants. METHODS: The REDINREN Pharmacogenetics Project was a multicenter study designed to evaluate the effect of DNA polymorphisms on Tac dose requirements. A total of 200 patients who received a first cadaveric kidney and Tac as primary immunosuppressive drug were genotyped for 96 DNA polymorphisms on 16 genes. Significant associations were further replicated in a second group of 200 patients. The Tac daily dose was adjusted to achieve a blood concentration of 10-15 ng/mL in the period 0-3 months PT, and 5-10 ng/mL thereafter. The dose of tacrolimus dose and blood concentrations were compared between genotypes at 1 week, 6 months, and 1 year PT. RESULTS: The CYP3A5 genotype (SNP rs776746) was the strongest predictor of Tac dose requirements. Patients who were CYP3A5*3*3 (CYP3A5 non-expressors) received significantly higher Tac dose at 1 week, 6 months, and 1 year PT (p<0.0001). At 1 week, 41% of the CYP3A5 non-expressors achieved target blood concentrations compared to 26% of the CYP3A5 expressors (p=0.007). We also found a significant effect of CYP3A4 genotype (SNP rs2740574) on Tac dose requirements in patients who were CYP3A5 non-expressors. None of the other polymorphisms were related to Tac dose requirements or modified the effect of the CYP3A5 genotype. CONCLUSIONS: rs776746 (CYP3A5) and rs2740574 (CYP3A4) were the only SNPs associated with Tac dosage. The genotyping of these polymorphisms could be a useful pharmacogenetic tool to determine the Tac dose immediately after transplantation.