Morikubo Hiromu, Kobayashi Taku, Ozaki Ryo, Okabayashi Shinji, Kuronuma Satoshi, Takeuchi Osamu, Shiba Tenyo, Kiyohara Hiroki, Matsubayashi Mao, Sagami Shintaro, Nakano Masaru, Ikezaki Osamu, Hisamatsu Tadakazu, Tanaka Yoichi, Hibi Toshifumi
Center for Advanced IBD Research and Treatment, Kitasato University Kitasato Institute Hospital, Tokyo, Japan.
Department of Gastroenterology and Hepatology, Kitasato University Kitasato Institute Hospital, Tokyo, Japan.
J Gastroenterol Hepatol. 2021 Aug;36(8):2116-2124. doi: 10.1111/jgh.15411. Epub 2021 Jan 29.
Thiopurines are often used in combination with mesalazine for the treatment of ulcerative colitis (UC). Mesalazine formulations are delivered to the digestive tract by various delivery systems and absorbed as 5-aminosalicylic acid (5-ASA). 5-ASA is known to inhibit thiopurine S-methyltransferase (TPMT) activity and to affect thiopurine metabolism. There have been no studies comparing TPMT inhibition by multimatrix mesalazine (MMX) with other formulations. We investigated the difference in TPMT inhibition by different mesalazine formulations and prospectively confirmed the clinical relevance.
Plasma concentrations of 5-ASA, N-acetyl-5-aminosalicylic acid (N-Ac-5-ASA), and TPMT activities were measured in UC patients receiving various mesalazine formulations (time-dependent or pH-dependent mesalazine or MMX) as monotherapy. Patients already on both time-dependent or pH-dependent mesalazine and thiopurines switched their mesalazine to MMX, examining 6-thioguanine nucleotide (6-TGN) and 6-methylmercaptopurine (6-MMP) 0 and 8 weeks after switching. Clinical relapse after switching was also monitored for 24 weeks.
Plasma 5-ASA and N-Ac-5-ASA levels were significantly higher in patients receiving time-dependent mesalazine (n = 12) compared with pH-dependent mesalazine (n = 12) and MMX (n = 15), accompanied by greater TPMT inhibition. Prospective switching from time-dependent mesalazine to MMX decreased 6-TGN levels, increased those of 6-MMP, and increased 6-MMP/6-TGN ratios. Furthermore, this resulted in significantly more relapses than switching from pH-dependent mesalazine to MMX.
Time-dependent mesalazine has higher plasma 5-ASA and N-Ac-5-ASA levels and greater TPMT inhibition than MMX. Therefore, switching from time-dependent mesalazine to MMX may lead to an increase of 6-MMP/6-TGN, which may reduce the clinical effectiveness of thiopurines, warranting close monitoring after switch.
硫嘌呤类药物常与美沙拉嗪联合用于治疗溃疡性结肠炎（UC）。美沙拉嗪制剂通过多种给药系统输送至消化道，并以5-氨基水杨酸（5-ASA）的形式被吸收。已知5-ASA可抑制硫嘌呤甲基转移酶（TPMT）的活性并影响硫嘌呤代谢。目前尚无研究比较多基质美沙拉嗪（MMX）与其他制剂对TPMT的抑制作用。我们研究了不同美沙拉嗪制剂对TPMT抑制作用的差异，并前瞻性地证实了其临床相关性。
对接受各种美沙拉嗪制剂（时间依赖性或pH依赖性美沙拉嗪或MMX）单药治疗的UC患者，测定其血浆中5-ASA、N-乙酰-5-氨基水杨酸（N-Ac-5-ASA）的浓度以及TPMT活性。已同时服用时间依赖性或pH依赖性美沙拉嗪和硫嘌呤类药物的患者将其美沙拉嗪换为MMX，在换药后0周和8周检测6-硫鸟嘌呤核苷酸（6-TGN）和6-甲基巯基嘌呤（6-MMP）。换药后还监测了24周的临床复发情况。
与接受pH依赖性美沙拉嗪（n = 12）和MMX（n = 15）的患者相比，接受时间依赖性美沙拉嗪（n = 12）的患者血浆5-ASA和N-Ac-5-ASA水平显著更高，同时TPMT抑制作用更强。从时间依赖性美沙拉嗪前瞻性地换为MMX可降低6-TGN水平，提高6-MMP水平，并增加6-MMP/6-TGN比值。此外，与从pH依赖性美沙拉嗪换为MMX相比，这导致更多的复发。
与MMX相比，时间依赖性美沙拉嗪的血浆5-ASA和N-Ac-5-ASA水平更高，对TPMT的抑制作用更强。因此，从时间依赖性美沙拉嗪换为MMX可能导致6-MMP/6-TGN升高，这可能会降低硫嘌呤类药物的临床疗效，换药后需密切监测。
