title: Impact of CYP3A5 genetic polymorphisms on the pharmacokinetics and short-term remission in patients with ulcerative colitis treated with tacrolimus.
abstract: OBJECTIVE
  The pharmacokinetics of tacrolimus (Tac) differ among individuals, and genetic polymorphisms of cytochrome P-450 (CYP) 3A4, CYP3A5, and ABCB1 are thought to be involved. The aim of this study was to clarify whether these genetic polymorphisms affect the pharmacokinetics of Tac in patients with ulcerative colitis.
  
  
  METHODS
  The subjects in this study were 45 patients with moderate-to-severe ulcerative colitis who were resistant to other therapies and were treated with Tac. The subjects were tested for genetic polymorphisms of CYP3A4, CYP3A5, and ABCB1, and the relationship between Tac pharmacokinetics and the remission rate was investigated.
  
  
  RESULTS
  Of the 45 subjects, 24 (53.3%) were CYP3A5 expressers (Exp), and 21 (46.7%) were non-expressers (Non-Exp). The trough level and the dose-adjusted trough level on days 2-5 were significantly higher in the Non-Exp group than in the Exp group (10.16 ± 5.84 vs 4.47 ± 2.50 ng/mL, P < 0.0001, 139.36 ± 77.43 vs 61.37 ± 41.55 ng/mL per mg/kg/day, P < 0.0001). The percentage of patients achieving the optimal trough level on days 2-5 was significantly higher in the Non-Exp group than in the Exp group (40.0% vs 4.3%, P = 0.01). This trend was also observed on days 7-10. On multivariate analysis, factors associated with achievement of the optimal trough level were food non-intake and Non-Exp of CYP3A5. The remission rate was significantly higher in the Non-Exp group than in the Exp group (47.6% vs 16.7%, P = 0.046).
  
  
  CONCLUSIONS
  CYP3A5 genetic polymorphisms affected the pharmacokinetics of Tac, so that the short-term clinical remission rate was different between Exp and Non-Exp of CYP3A5.
authors.affiliation: Department of Gastroenterology, Fukuoka University Chikushi Hospital, Chikushino, Fukuoka, Japan.
authors.forename: Fumihito
authors.initials: F
authors.lastname: Hirai
authors.forename: Noritaka
authors.initials: N
authors.lastname: Takatsu
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Yano
authors.forename: Yuhou
authors.initials: Y
authors.lastname: Satou
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Takahashi
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ishikawa
authors.forename: Kozue
authors.initials: K
authors.lastname: Tsurumi
authors.forename: Takashi
authors.initials: T
authors.lastname: Hisabe
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Matsui
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000328:Adult; D044466:Asian People; D003093:Colitis, Ulcerative / Q000188:drug therapy* / Q000235:genetics*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics*; D012074:Remission Induction; D016559:Tacrolimus / Q000493:pharmacokinetics* / Q000627:therapeutic use*
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007166:Immunosuppressive Agents; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D016559:Tacrolimus
keywords: ABCB1; CYP3A4; CYP3A5; tacrolimus; ulcerative colitis