@article{df7b6ab35cbf47b99f2aba60802991a7,
title = "Differential effects of mesalazine formulations on thiopurine metabolism through thiopurine S-methyltransferase inhibition",
abstract = "Background and Aim: 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. Methods: 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. Results: 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. Conclusions: 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.",
keywords = "mesalazine, therapeutic drug monitoring, thiopurine, ulcerative colitis",
author = "Hiromu Morikubo and Taku Kobayashi and Ryo Ozaki and Shinji Okabayashi and Satoshi Kuronuma and Osamu Takeuchi and Tenyo Shiba and Hiroki Kiyohara and Mao Matsubayashi and Shintaro Sagami and Masaru Nakano and Osamu Ikezaki and Tadakazu Hisamatsu and Yoichi Tanaka and Toshifumi Hibi",
note = "Funding Information: Hiromu Morikubo has received research funding from Japan Foundation for Applied Enzymology. Taku Kobayashi has served as a speaker, a consultant, or an advisory role for AbbVie, Ajinomoto Pharma, Asahi Kasei Medical, Astellas, Alfresa Pharma, Celltrion, Covidien, EA Pharma, Eisai, Eli Lilly, Ferring Pharmaceuticals, Gilead Sciences, Janssen, JIMRO, Kyorin Pharmaceutical, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Nippon Kayaku, Pfizer, Takeda Pharmaceutical, Thermo Scientific, and Zeria Pharmaceutical and received researching fund from Abbvie, EA Pharma, Otsuka Holdings, Zeria Pharmaceutical, Kyorin Pharmaceutical, Mochida Pharmaceutical, Thermo Fisher Scientific, Alfresa Pharma, Nippon Kayaku, Asahi Kasei Medical, and Sekisui Medical. Hiroki Kiyohara has received research funding from Mitsubishi Tanabe Pharma. Shintaro Sagami has served as a speaker for AbbVie, Takeda Pharmaceutical, and Zeria Pharmaceutical and has received research funding from Japan Foundation for Applied Enzymology and an endowed chair from AbbVie, JIMRO, Zeria Pharmaceutical, Kyorin Pharmaceutical, Mochida Pharmaceutical, and EA Pharma. Masaru Nakano has received a grant from Mitsubishi Tanabe Pharma and Japanese Foundation for Research and Promotion of Endoscopy and received consulting fees from Medtronic, Takeda Pharmaceutical, Kyorin Pharmaceutical, Mochida Pharmaceutical, and Zeria Pharmaceutical. Tadakazu Hisamatsu has served as a speaker, a consultant, or an advisory role for Celgene K.K., Janssen, Pfizer, Mitsubishi Tanabe Pharma, Nichi‐Iko Pharmaceutical, and Takeda Pharmaceutical and has received research funding from EA Pharma, AbbVie, Celgene K.K., Janssen, Pfizer, Mitsubishi Tanabe Pharma, Kyorin Pharmaceutical, JIMRO, Mochida Pharmaceutical, Nichi‐Iko Pharmaceutical, Daiichi Sankyo, and Takeda Pharmaceutical. Toshifumi Hibi has served as a speaker, a consultant, or an advisory role for Aspen Japan K.K., JIMRO, AbbVie, Takeda Pharmaceutical, Zeria Pharmaceutical, Mitsubishi Tanabe Pharma, Kyorin Pharmaceutical, Ferring, Gilead Sciences, Janssen, Kissei Pharmaceutical, Mochida Pharmaceutical, Nippon Kayaku, Pfizer, Bristol‐Myers Squibb, Celltrion, EA Pharma, Eli Lilly, and Nichi‐Iko Pharmaceutical and has received research funding from AbbVie, JIMRO, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Takeda Pharmaceutical, Zeria Pharmaceutical, Kyorin Pharmaceutical, and Otsuka Holdings. None of the above represents a conflict of interest for this paper. Declaration of conflict of interest: Funding Information: This work was partly supported by the Japan Foundation for Applied Enzymology (grant number 18S006). No funding was received from any other organization for this work. Financial support: Publisher Copyright: {\textcopyright} 2021 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd",
year = "2021",
month = aug,
doi = "10.1111/jgh.15411",
language = "English",
volume = "36",
pages = "2116--2124",
journal = "Journal of Gastroenterology and Hepatology (Australia)",
issn = "0815-9319",
publisher = "Wiley-Blackwell",
number = "8",
}