Impact of CYP3A5 Genetic Polymorphisms on the Pharmacokinetics and Short-term Remission in Patients With Ulcerative Colitis Treated With Tacrolimus

Fumihito Hirai; Noritaka Takatsu; Yutaka Yano; Yuhou Satou; Haruhiko Takahashi; Satoshi Ishikawa; Kozue Tsurumi; Takashi Hisabe; Toshiyuki Matsui


J Gastroenterol Hepatol. 2014;29(1):60-66. 

In This Article

Abstract and Introduction


Background and Aim 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.


In recent years, the calcineurin inhibitor tacrolimus (Tac) has been widely used internationally as an immunosuppressant in organ transplantation patients.[1] In a double-blind trial in Japan, Tac was also shown to be safe and effective in ulcerative colitis (UC) patients with moderate-to-severe activity.[2] In Japan, Tac has been used as remission induction therapy in UC patients since 2009. One characteristic of Tac is that its effect is trough level-dependent.[2,3] Tac metabolism is affected by various factors, including food intake/non-intake, drug metabolism enzymes, and transporters.[4,5] This means that the blood level of Tac varies considerably among individual patients, and therapeutic drug monitoring (TDM) is needed to safely obtain a good therapeutic effect.[6] In terms of drug metabolism enzymes and transporters, Tac is a substrate of cytochrome P-450 (CYP) 3A enzyme and drug transporter ATP-binding cassette sub-family B member 1 (ABCB1).[4] Both CYP3A4 and CYP3A5 are known to be involved in the metabolism of Tac,[7] and there are many reports on the relationship between Tac pharmacokinetics and genetic polymorphisms of CYP3A4, CYP3A5, and ABCB1 in organ transplantation patients.[8–11] However, there has been no investigation of these genetic polymorphisms and Tac pharmacokinetics in inflammatory bowel disease (IBD) patients, and only one report on the response to Tac therapy.[12] Genetic polymorphisms are known to exist in CYP3A4, CYP3A5, and ABCB1, and there are also known to be large differences among ethnic groups.[9–11] In general, CYP3A5 genetic polymorphisms, namely, expressers (Exp) with *1 or non-expressers (Non-Exp) without *1, are thought to have the greatest effect on Tac pharmacokinetics.[13,14] In the present study, CYP3A4, CYP3A5, and ABCB1 genetic polymorphisms and their potential associations with Tac pharmacokinetics and efficacy were analyzed in Japanese IBD patients.