Which Genetic Determinants Should be Considered for Tacrolimus Dose Optimization in Kidney Transplantation? A Combined Analysis of Genes Affecting the CYP3A Locus.

摘要: Background: Tacrolimus is established as immunosuppressant after kidney transplantation. Polymorphism of the cytochrome P450 3A5 (CYP3A5) gene contributes significantly to tacrolimus dose requirements. Recently, CYP3A4*22 was reported additionally affect pharmacokinetics (PK). In addition, there are further polymorphic genes, possibly influencing CYP3A activity [pregnane x receptor NR1I2, oxidoreductase (POR), and peroxisome proliferator-activator alpha (PPARA)]. We aimed investigate combined effects these variants on maintenance PK in patients with stable transplantation 2 study centers. Methods: A total 223 white (German cohort, 136; Danish 87) included genotyped for CYP3A5 (rs776746), CYP3A4 (rs35599367), NR1I2 (rs2276707), POR (rs1057868), PPARA (rs4253728). Dosage trough concentration/dose ratios were considered separately. subset investigated comprehensive parameters. Results: dose, concentration, ratio did not differ between German cohort. CYP3A5*3 contributed requirements only Homozygous carriers both required 4.8 +/- 3.1 mg, whereas wild types 165% higher mean doses 12.5 7.7 P = 1.4 10(-5)). The investigation revealed nonsignificant impact genotypes AUC12h nonexpressers (P 0.079, power 57%). For entire sample, final multiple linear regression model CYP3A5, CYP3A4, age. It explained 18.3% interindividual variability 8.8 10(-10)). Conclusions: Therapeutic drug monitoring remains essential clinical care Genotyping however, could facilitate rapid finding adapt appropriate other genetic factors had little or no effect.