title: Impact of the CYP3A4*1G polymorphism and its combination with CYP3A5 genotypes on tacrolimus pharmacokinetics in renal transplant patients.
abstract: OBJECTIVE
  Tacrolimus is a substrate of CYP3A4 and CYP3A5. The present study investigated the impact of the CYP3A4*1/*1G polymorphism compared with CYP3A5 genotypes on the dose-adjusted pharmacokinetics of tacrolimus. The effects of the polymorphism on the variability in tacrolimus pharmacokinetics among patients with the CYP3A5*1 allele (CYP3A5 expresser) and among those with CYP3A5*3/*3 genotype (nonexpresser) were also studied.
  
  
  METHODS
  A total of 136 renal allograft recipients were given repeated doses of tacrolimus every 12 h. On day 28 after the renal transplantation, blood tacrolimus concentrations were measured, and dose-adjusted pharmacokinetics were determined and compared with the corresponding genotype.
  
  
  RESULTS
  The dose-adjusted AUC₀₋₁₂ and C₀ of tacrolimus were significantly lower in patients with the CYP3A4*1G allele and CYP3A5 expressers than those with the CYP3A4*1/*1 genotype and nonexpressers, respectively. In a multiple regression analysis, the dose-adjusted AUC₀₋₁₂ and C₀ values were associated with CYP3A4*1/*1 (p = 0.018 and 0.040, respectively) and CYP3A5*3/*3 (p < 0.001 each). The standardized regression coefficient for the AUC₀₋₁₂ of tacrolimus was approximately twofold less for CYP3A4*1/*1 than CYP3A5*3/*3. The lowest dose-adjusted AUC₀₋₁₂ was found in CYP3A5 expressers with the CYP3A4*1G allele.
  
  
  CONCLUSIONS
  The CYP3A4*1/*1G polymorphism was associated with the pharmacokinetics of tacrolimus, however, its contribution to dose-adjusted pharmacokinetics was approximately twofold less than that of the CYP3A5*1/*3 polymorphism. Although its effect on CYP3A4 activity is not clear, CYP3A4*1/*1G may be a candidate for a polymorphism affecting the interindividual variability in tacrolimus pharmacokinetics among CYP3A5 expressers.
authors.affiliation: Akita University School of Medicine, 1-1-1 Hondo, Akita 010-8543, Japan.
authors.forename: Masatomo
authors.initials: M
authors.lastname: Miura
authors.forename: Shigeru
authors.initials: S
authors.lastname: Satoh
authors.forename: Hideaki
authors.initials: H
authors.lastname: Kagaya
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Saito
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Numakura
authors.forename: Norihiko
authors.initials: N
authors.lastname: Tsuchiya
authors.forename: Tomonori
authors.initials: T
authors.lastname: Habuchi
mesh_terms: D000328:Adult; D000368:Aged; D054316:Biomarkers, Pharmacological; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D055106:Genome-Wide Association Study; D006239:Haplotypes; D006801:Humans; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D016559:Tacrolimus / Q000493:pharmacokinetics* / Q000627:therapeutic use
chemical_list: D054316:Biomarkers, Pharmacological; D007166:Immunosuppressive Agents; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D016559:Tacrolimus