ABCB1 single-nucleotide polymorphisms determine tacrolimus response in patients with ulcerative colitis

• Published in: Clinical pharmacology and therapeutics Vol. 89; no. 3; p. 422
• Main Authors: Herrlinger, K R, Koc, H, Winter, S, Teml, A, Stange, E F, Fellermann, K, Fritz, P, Schwab, M, Schaeffeler, E
• Format: Journal Article
• Language: English
• Published: United States 01.03.2011
• Subjects: Adolescent; Adult; Aged; Alleles; ATP Binding Cassette Transporter, Sub-Family B; ATP-Binding Cassette, Sub-Family B, Member 1 - genetics; Colitis, Ulcerative - drug therapy; Colitis, Ulcerative - physiopathology; Cytochrome P-450 CYP3A - genetics; Female; Follow-Up Studies; Humans; Immunosuppressive Agents - pharmacokinetics; Immunosuppressive Agents - pharmacology; Immunosuppressive Agents - therapeutic use; Logistic Models; Male; Middle Aged; Multivariate Analysis; Polymorphism, Single Nucleotide; Remission Induction - methods; Tacrolimus - pharmacokinetics; Tacrolimus - pharmacology; Tacrolimus - therapeutic use; Treatment Outcome; Young Adult
• ISSN: 1532-6535
• DOI: 10.1038/clpt.2010.348

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.