Abstract
Tacrolimus (Tac) is an effective remission inducer of refractory ulcerative colitis (UC). Gene polymorphisms result in interindividual variability in Tac pharmacokinetics. In this study, we aimed to examine the relationships between gene polymorphisms and the metabolism, pharmacokinetics, and therapeutic effects of Tac in patients with UC. Forty-five patients with moderate-to-severe refractory UC treated with Tac were retrospectively enrolled. Genotyping for cytochrome P450 (CYP) 3A4*1G, CYP3A5*3, CYP2C19*2, CYP2C19*3, nuclear receptor subfamily 1 group I member 2 (NR1I2)-25385C>T, ATP-binding cassette subfamily C member 2 (ABCC2)-24C>T, ABCC2 1249G>A, and ABCC2 3972C>T was performed. Concentration/dose (C/D) ratio, clinical therapeutic effects, and adverse events were evaluated. The C/D ratio of Tac in UC patients with the CYP3A4*1G allele was statistically lower than in those with the CYP3A4*1/*1 allele (P = 0.005) and significantly lower in patients with CYP3A5*3/*3 than in those with CYP3A5*1 (P < 0.001). Among patients with the CYP3A4*1G allele, the C/D ratio was significantly lower in patients with CYP3A5*1 than in those with CYP3A5*3/*3 (P = 0.001). Patients with the NR1I2-25385C/C genotype presented significantly more overall adverse events than those with the C/T or T/T genotype (P = 0.03). Although CYP3A4*1G and CYP3A5*3 polymorphisms were related to Tac pharmacokinetics, CYP3A5 presented a stronger effect than CYP3A4. The NR1I2-25385C/C genotype was related to the overall adverse events. The evaluation of these polymorphisms could be useful in the treatment of UC with Tac.
Highlights
Ulcerative colitis (UC), a chronic inflammatory disease of unknown etiology, occurs in the colorectum [1]
Other treatments were antitumor necrosis factor (TNF)-α antibodies in seven patients (16%) and thiopurines in eight patients (18%)
We investigated the interaction effect between CYP3A4 1G and CYP3A5 3 polymorphisms on Tac pharmacokinetics, as there was a strong degree of pair-wise linkage disequilibrium (LD) between CYP3A5 3 and CYP3A4 1G polymorphisms (S1 Table)
Summary
Ulcerative colitis (UC), a chronic inflammatory disease of unknown etiology, occurs in the colorectum [1]. Corticosteroid therapy is the mainstay option for inducing UC remission, 33% of severe active UC cases have been reported to be refractory to corticosteroids [2]. Calcineurin inhibitors such as cyclosporine and tacrolimus (Tac) [3] are effective remission. Cytochrome P450 3A polymorphisms and tacrolimus pharmacokinetics
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