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  • Title: Genetic polymorphisms and individualized tacrolimus dosing.
    Author: López-Montenegro Soria MA, Kanter Berga J, Beltrán Catalán S, Milara Payá J, Pallardó Mateu LM, Jiménez Torres NV.
    Journal: Transplant Proc; 2010 Oct; 42(8):3031-3. PubMed ID: 20970601.
    Abstract:
    BACKGROUND: Genetic polymorphisms of metabolism enzymes or intestinal drug transporters may affect pharmacokinetic responses to immunosuppressive drugs in renal transplant recipients. We sought to identify the frequency of genetic polymorphisms and their importance for individualization of tacrolimus doses. PATIENTS AND METHODS: We performed an observational study in 35 renal transplant recipients treated with tacrolimus, mycophenolate mofetil, and corticosteroids. Tacrolimus concentrations were determined by immunoanalysis (IMx method; Abbott Diagnostics, Abbott Park, Ill), on 11 blood samples per patient during the first 6 weeks after renal transplantation. For each patient, we calculated the mean value and its standard error (SEM) of the concentration/dose ratio (ng/mL/mg) of tacrolimus. The pharmacogenetic analysis included single nucleotide polymorphisms (SNPs) in the CYP3A5 (CYP3A5*3 (A6986G), CYP3A5*6 (G14690A), MDR1 (C3435T and G2677T/A) and PXR (C-25385T) genes. RESULTS: Of the patients, 62.8% (n=22) were men and the overall mean age was 55 years (95% confidence interval, 48.7-62.7). The SNP distribution was: CYP3A5*3: G/G=82.9%, A/G=17.1%; CYP3A5*6: G/G=88.6%, G/A=11.4%; MDR1 C3435T: C/C=25.7%, C/T=62.9%, T/T=11.4%; for MDR1 G2677T/A: G/G=22.9%, G/T=65.7%, T/T=11.4% and for PXR: C/T=85.7%, T/T=14.3%. Tacrolimus concentration/dose ratios in heterozygote patients for CYP3A5*3 genotypes was >120% lower than for the homozygote CYP3A5*3 genotype (0.65±0.04 vs 1.45±0.05; P<.0001). Wild-type MDR1 (3435 C/C) genotype patients showed up to 40% lower concentration/dose ratios compared with heterozygote and homozygote genotypes (C/C; 1±0.07 vs C/T; 1.4±0.06 vs T/T; 1.37±0.09; P<.0001). CONCLUSION: Intestinal absorption and metabolism of tacrolimus was significantly affected by the SNPs in the CYP3A5 and MDR1 genes, which may offer a useful tool to optimize tacrolimus dosing after renal transplantation.
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