title: The effect of CYP3A5 genetic polymorphisms on adverse events in patients with ulcerative colitis treated with tacrolimus.
abstract: BACKGROUND
  Tacrolimus is an immunosuppressive agent, used in the remission induction therapy of ulcerative colitis (UC).
  
  
  OBJECTIVE
  We investigated the correlation between CYP3A5 genetic polymorphisms and the adverse events in patients with UC. The pharmacokinetics of tacrolimus after oral administration were also analyzed.
  
  
  METHODS
  We enrolled 29 hospitalized patients with UC received oral tacrolimus. Genotyping for CYP3A5 A6986G (rs776746) was performed using Custom TaqMan®SNP genotyping assays. Adverse events, concentration and dose (C/D) ratios and clinical outcomes were investigated.
  
  
  RESULTS
  CYP3A5 expressers and non-expressers were 16 and 13, respectively. C/D ratios of CYP3A5 expressers were significantly lower compared to non-expressers. The response rate in CYP3A5 non-expressers was relatively higher in the early phase of treatment compared to expressers, but not statistically significant. The incidence of overall adverse events was significantly higher in CYP3A5 expressers than in non-expressers (P=0.034, chi-squared test). In particular, the incidence of nephrotoxicity was significantly higher in CYP3A5 expressers compared to non-expressers (P=0.027, chi-squared test). All of the nephrotoxicity were reversible and resolved by discontinuation or dose reduction of tacrolimus.
  
  
  CONCLUSIONS
  The adverse events especially nephrotoxicity were frequently observed in CYP3A5 expressers. CYP3A5 expressers should be paid attention to the onset of nephrotoxicity.
authors.affiliation: Department of Medicine, Shiga University of Medical Science, Otsu, Japan.
authors.forename: Ayumi
authors.initials: A
authors.lastname: Asada
authors.affiliation: Department of Medicine, Shiga University of Medical Science, Otsu, Japan. Electronic address: sb@belle.shiga-med.ac.jp.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Bamba
authors.affiliation: Department of Medicine, Shiga University of Medical Science, Otsu, Japan.
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Morita
authors.affiliation: Department of Medicine, Shiga University of Medical Science, Otsu, Japan.
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Takahashi
authors.affiliation: Department of Medicine, Shiga University of Medical Science, Otsu, Japan.
authors.forename: Hirotsugu
authors.initials: H
authors.lastname: Imaeda
authors.affiliation: Department of Medicine, Shiga University of Medical Science, Otsu, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nishida
authors.affiliation: Department of Medicine, Shiga University of Medical Science, Otsu, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Inatomi
authors.affiliation: Department of Medicine, Shiga University of Medical Science, Otsu, Japan.
authors.forename: Mitsushige
authors.initials: M
authors.lastname: Sugimoto
authors.affiliation: Department of Medicine, Shiga University of Medical Science, Otsu, Japan.
authors.forename: Masaya
authors.initials: M
authors.lastname: Sasaki
authors.affiliation: Department of Medicine, Shiga University of Medical Science, Otsu, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Andoh
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced*; D003093:Colitis, Ulcerative / Q000188:drug therapy*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects* / Q000493:pharmacokinetics; D008297:Male; D020641:Polymorphism, Single Nucleotide; D016559:Tacrolimus / Q000009:adverse effects* / Q000493:pharmacokinetics; D016896:Treatment Outcome
chemical_list: D007166:Immunosuppressive Agents; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus
keywords: Adverse events; Nephrotoxicity; Single nucleotide polymorphism