title: ABCB1 single-nucleotide polymorphisms determine tacrolimus response in patients with ulcerative colitis.
abstract: Tacrolimus (Tac) is effective in the treatment of steroid-refractory ulcerative colitis (UC); however, nonresponse and unpredictable side effects are major limitations. Because Tac response in patients who have undergone solid-organ transplantation has been associated with the presence of variants in CYP3A and ABCB1, we elucidated the contributions of CYP3A4*1B and CYP3A5*3 and of ABCB1 1236C>T, 2677G>T,A, and 3435C>T polymorphisms to Tac response in 89 patients with UC. Short-term remission and response were achieved in 61 and 14% of the patients, respectively, and were associated with colectomy-free survival. In a linear logistic regression model, patients with homozygous variants for one of the three ABCB1 alleles showed significantly higher short-term remission rates as compared with those of other genotypes. The effects held true after multivariate analysis including multiple comparisons and were more pronounced after correction for dose-adjusted Tac blood trough levels. We suggest that ABCB1, but not CYP3A5, may predict short-term remission of Tac in steroid-refractory UC.
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Robert-Bosch-Hospital, Stuttgart, Germany. klaus.herrlinger@rbk.de
authors.forename: K R
authors.initials: KR
authors.lastname: Herrlinger
authors.forename: H
authors.initials: H
authors.lastname: Koc
authors.forename: S
authors.initials: S
authors.lastname: Winter
authors.forename: A
authors.initials: A
authors.lastname: Teml
authors.forename: E F
authors.initials: EF
authors.lastname: Stange
authors.forename: K
authors.initials: K
authors.lastname: Fellermann
authors.forename: P
authors.initials: P
authors.lastname: Fritz
authors.forename: M
authors.initials: M
authors.lastname: Schwab
authors.forename: E
authors.initials: E
authors.lastname: Schaeffeler
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D003093:Colitis, Ulcerative / Q000188:drug therapy* / Q000503:physiopathology; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D020641:Polymorphism, Single Nucleotide; D012074:Remission Induction / Q000379:methods; D016559:Tacrolimus / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome; D055815:Young Adult
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; D016559:Tacrolimus