Abstract
Tacrolimus has been used to induce remission in patients with steroid-refractory ulcerative colitis. It poses a problem of large individual differences in dosage necessary to attain target blood concentration and, often, this leads to drug inefficacy. We examined the difference in mRNA expression levels of ATP binding cassette transporter B1 (ABCB1) between inflamed and non-inflamed tissues, and the influence of CYP3A5 genotype on tacrolimus therapy. The mRNA expression of CYP3A4 in colonic mucosa and that of cytochrome p450 3A5 (CYP3A5) and ABCB1 in inflamed and non-inflamed areas were examined in 14 subjects. The mRNA expression levels of CYP3A5 were higher than that of CYP3A4. The mRNA expression of ABCB1 was lower in the inflamed than in the non-inflamed mucosa, despite that of CYP3A5 mRNA level being not significantly changed. Hence, the deterioration of the disease is related to the reduction of the barrier in the inflamed mucosa. The relationship between CYP3A5 genotype and blood concentration, dose, and concentration/dose (C/D) ratio of tacrolimus in 15 subjects was studied. The tacrolimus dose to maintain equivalent blood concentrations was lower in CYP3A5*3/*3 than in CYP3A5*1 carriers, and the C/D ratio was significantly higher in the latter. Thus, CYP3A5 polymorphism information played a role in determining the initial dose of tacrolimus. Furthermore, since the effect of tacrolimus appears earlier in CYP3A5*3/*3 than in CYP3A5*1/*1 and *1/*3, it seems necessary to change the evaluation time of therapeutic effect by CYP3A5 genotype. Additionally, the relationship between CYP3A5 genotype and C/D ratio of tacrolimus in colonic mucosa was investigated in 10 subjects. Tacrolimus concentration in the mucosa was two-fold higher in CYP3A5*3/*3 than in CYP3A5*1 carriers, although no significant difference in tacrolimus-blood levels was observed. Therefore, the local concentration of tacrolimus affected by CYP3A5 polymorphism might be related to its therapeutic effect.
Highlights
5-aminosalicylic acid (5-ASA or mesalazine), steroids, calcineurin inhibitors, etc., have been used to treat ulcerative colitis (UC) [1,2]
The mRNA expression of ATP binding cassette transporter B1 (ABCB1) was reduced in the inflamed regions as opposed to the non-inflamed regions in patients
Our study revealed that the mRNA expression level of cytochrome p450 3A5 (CYP3A5) was higher than that of cytochrome p450 3A4 (CYP3A4) in non-inflamed colonic mucosa in healthy subjects, [33] and in UC patients (Figure 1A)
Summary
5-aminosalicylic acid (5-ASA or mesalazine), steroids, calcineurin inhibitors, etc., have been used to treat ulcerative colitis (UC) [1,2]. The NFAT-induced transcription of interleukin 2 and interferon γ in the nucleus is inhibited These cytokines promote the proliferation of helper T-cells; tacrolimus suppresses T-cell proliferation and exerts its immunosuppressive activity [6,7]. A decrease in Pgp is considered as to be responsible for altering the pharmacokinetics of tacrolimus, but is attributed to the worsening of the disease condition of UC [26,27] Based on these backgrounds, the relationship between the degree of inflammation and ABCB1 mRNA-expression level was used as a positive control for the sampling of biopsy specimens for examining the mRNA expression levels of CYP3A4 and CYP3A5 in mucosal tissues
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