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Genetic polymorphisms of CYP3A genes affect cyclosporine a blood concentration and dose requirement in transplant recipients
Cyclosporine A (CsA), mainly metabolized by cytochrome P450 (CYP) 3A, presents a wide interindividual variability in its kinetics. CYP3A4 and CYP3A5 are members of the CYP3A family. The presence of two CYP3A5*3 alleles results in an absence of CYP3A5 activity (CYP3A5 non expressors), while that of CYP3A4*1B allele results in an increased CYP3A4 activity. Our aim was to study the influence of CYP3A5*3 and CYP3A4*1B polymorphisms on CsA daily dose and trough blood concentrations. CsA daily dose and trough blood concentrations (measured by EMIT) were obtained at month 1, 3, 6 and 12 after transplantation from 70 Caucasian, renal or lung transplant recipients. CYP3A5*3 and CYP3A4*1B genotypes were determined by TaqMan. Log-transformed data from genotype groups were compared by t-test. CsA dose and weight-adjusted trough concentrations were significantly higher in CYP3A5 non expressors (*3/*3; n=56-59) than in CYP3A5 expressors (*1/*1 and *1/*3; n=10-11). CYP3A5 non expressors presented a 1.3-fold (CI95%=1.0-1.6; p=0.04), 1.6-fold (CI95%=1.3-2.1; p=0.0005) and 1.3-fold (CI95%=1.0-1.6; p=0.04) increase in dose and weight-adjusted trough concentrations at 3, 6 and 12 months after transplantation, respectively. Furthermore, CsA dose requirements were significantly higher in CYP3A5 expressors than in CYP3A5 non expressors. CYP3A5 expressors presented a 1.3-fold (CI95%=1.0-1.6; p=0.02), 1.3-fold (CI95%=1.1-1.7; p=0.01), 1.4- fold (CI95%=1.1-1.7; p=0.006) and 1.5-fold (CI95%=1.2-1.8; p=0.001) increase in CsA daily dose per weight at 1, 3, 6 and 12 months after transplantation, respectively. The three CYP3A4 *1/*1B patients presented significantly lower CsA dose and weight-adjusted trough concentrations (0.6-fold at 12 months; p=0.02) and higher daily doses (2-fold at 12 months; p=0.0007), but since they were all CYP3A5 expressors, no statement can be made. In conclusion, these data indicate that genotyping of CYP3A5 allele could be a useful tool, combined with therapeutic drug monitoring, to optimize CsA dosing in transplant recipients.
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