Differential effects of mesalazine formulations on thiopurine metabolism through thiopurine S-methyltransferase inhibition.
mesalazine
therapeutic drug monitoring
thiopurine
ulcerative colitis
Journal
Journal of gastroenterology and hepatology
ISSN: 1440-1746
Titre abrégé: J Gastroenterol Hepatol
Pays: Australia
ID NLM: 8607909
Informations de publication
Date de publication:
Aug 2021
Aug 2021
Historique:
revised:
08
12
2020
received:
21
08
2020
accepted:
05
01
2021
pubmed:
21
1
2021
medline:
22
12
2021
entrez:
20
1
2021
Statut:
ppublish
Résumé
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.
Sections du résumé
BACKGROUND AND AIM
OBJECTIVE
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
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
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
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.
Substances chimiques
Anti-Inflammatory Agents, Non-Steroidal
0
Azathioprine
MRK240IY2L
Mercaptopurine
E7WED276I5
Mesalamine
4Q81I59GXC
Methyltransferases
EC 2.1.1.-
thiopurine methyltransferase
EC 2.1.1.67
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
2116-2124Subventions
Organisme : Japan Foundation for Applied Enzymology
ID : 18S006
Informations de copyright
© 2021 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.
Références
Hibi T, Ogata H. Novel pathophysiological concepts of inflammatory bowel disease. J. Gastroenterol. 2006; 41: 10-16.
Cosnes J, Gower-Rousseau C, Seksik P, Cortot A. Epidemiology and natural history of inflammatory bowel diseases. Gastroenterology 2011; 140: 1785-1794.
Asakura K, Nishiwaki Y, Inoue N, Hibi T, Watanabe M, Takebayashi T. Prevalence of ulcerative colitis and Crohn's disease in Japan. J. Gastroenterol. 2009; 44: 659-665.
Naganuma M, Sakuraba A, Hibi T. Ulcerative colitis: prevention of relapse. Expert Rev. Gastroenterol. Hepatol. 2013; 7: 341-351.
Matsuoka K, Kobayashi T, Ueno F et al. Evidence-based clinical practice guidelines for inflammatory bowel disease. J. Gastroenterol. 2018; 53: 305-353.
van Gennep S, de Boer NK, D'Haens GR, Lowenberg M. Thiopurine treatment in ulcerative colitis: a critical review of the evidence for current clinical practice. Inflamm. Bowel Dis. 2017; 24: 67-77.
Gisbert JP, Linares PM, McNicholl AG, Mate J, Gomollon F. Meta-analysis: the efficacy of azathioprine and mercaptopurine in ulcerative colitis. Aliment. Pharmacol. Ther. 2009; 30: 126-137.
Dubinsky MC, Lamothe SP, Yang HY et al. Pharmacogenomics and metabolite measurement for 6-mercaptopurine therapy in inflammatory bowel disease. Gastroenterology 2000; 118: 705-713.
Bradford K, Shih DQ. Optimizing 6-mercaptopurine and azathioprine therapy in the management of inflammatory bowel disease. World J. Gastroenterol. 2011; 17: 4166-4173.
Schwab M, Schäffeler ES, Marx C et al. Azathioprine therapy and adverse drug reactions in patients with inflammatory bowel disease: impact of thiopurine S-methyltransferase polymorphism. Pharmacogenetics 2002; 12: 429-436.
Lowry PW, Franklin CL, Weaver AL et al. Leucopenia resulting from a drug interaction between azathioprine or 6-mercaptopurine and mesalamine, sulphasalazine, or balsalazide. Gut 2001; 49: 656-664.
Gao X, Zhang FB, Ding L et al. The potential influence of 5-aminosalicylic acid on the induction of myelotoxicity during thiopurine therapy in inflammatory bowel disease patients. Eur. J. Gastroenterol. Hepatol. 2012; 24: 958-964.
Watanabe M, Hanai H, Nishino H, Yokoyama T, Terada T, Suzuki Y. Comparison of QD and TID oral mesalazine for maintenance of remission in quiescent ulcerative colitis: a double-blind, double-dummy, randomized multicenter study. Inflamm. Bowel Dis. 2013; 19: 1681-1690.
Ito H, Iida M, Matsumoto T et al. Direct comparison of two different mesalamine formulations for the maintenance of remission in patients with ulcerative colitis: a double-blind, randomized study. Inflamm. Bowel Dis. 2010; 16: 1575-1582.
Ogata H, Yokoyama T, Mizushima S, Hagino A, Hibi T. Comparison of efficacy of once daily multimatrix mesalazine 2.4 g/day and 4.8 g/day with other 5-aminosalicylic acid preparation in active ulcerative colitis: a randomized, double-blind study. Intest Res 2018; 16: 255-266.
Ye B, van Langenberg DR. Mesalazine preparations for the treatment of ulcerative colitis: are all created equal? World J. Gastrointest. Pharmacol. Ther. 2015; 6: 137-144.
Sandborn WJ, Hanauer SB. Systematic review: the pharmacokinetic profiles of oral mesalazine formulations and mesalazine pro-drugs used in the management of ulcerative colitis. Aliment. Pharmacol. Ther. 2003; 17: 29-42.
Nardelli S, Pisani LF, Tontini GE, Vecchi M, Pastorelli L. MMX® technology and its applications in gastrointestinal diseases. Therap. Adv. Gastroenterol. 2017; 10: 545-552.
Sandborn WJ. Oral 5-ASA therapy in ulcerative colitis: what are the implications of the new formulations? J. Clin. Gastroenterol. 2008; 42: 338-344.
Bohm SK, Kruis W. Long-term efficacy and safety of once-daily mesalazine granules for the treatment of active ulcerative colitis. Clin Exp Gastroenterol 2014; 7: 369-383.
Abinusawa A, Tenjarla S. Release of 5-aminosalicylic acid (5-ASA) from mesalamine formulations at various pH levels. Adv. Ther. 2015; 32: 477-484.
Goyanes A, Hatton GB, Merchant HA, Basit AW. Gastrointestinal release behaviour of modified-release drug products: dynamic dissolution testing of mesalazine formulations. Int. J. Pharm. 2015; 484: 103-108.
Tenjarla S. Dissolution of commercially available mesalamine formulations at various pH levels. Drugs R D 2015; 15: 211-215.
Wiwattanakul S, Prommas S, Jenjirattithigarn N et al. Development and validation of a reliable method for thiopurine methyltransferase (TPMT) enzyme activity in human whole blood by LC-MS/MS: an application for phenotypic and genotypic correlations. J. Pharm. Biomed. Anal. 2017; 145: 758-764.
Ito H, Iida M, Matsumoto T et al. Direct comparison of two different mesalamine formulations for the induction of remission in patients with ulcerative colitis: a double-blind, randomized study. Inflamm. Bowel Dis. 2010; 16: 1567-1574.
Wang Y, Parker CE, Feagan BG, MacDonald JK. Oral 5-aminosalicylic acid for maintenance of remission in ulcerative colitis. Cochrane Database Syst. Rev. 2016:CD000544.
Ogata H, Aoyama N, Mizushima S, Hagino A, Hibi T. Comparison of efficacy of multimatrix mesalazine 4.8 g/day once-daily with other high-dose mesalazine in active ulcerative colitis: a randomized, double-blind study. Intest Res 2017; 15: 368-379.
D'Inca R, Paccagnella M, Cardin R et al. 5-ASA colonic mucosal concentrations resulting from different pharmaceutical formulations in ulcerative colitis. World J. Gastroenterol. 2013; 19: 5665-5670.
Yu A, Baker JR, Fioritto AF et al. Measurement of in vivo gastrointestinal release and dissolution of three locally acting mesalamine formulations in regions of the human gastrointestinal tract. Mol. Pharm. 2017; 14: 345-358.
Xin H, Fischer C, Schwab M, Klotz U. Effects of aminosalicylates on thiopurine S-methyltransferase activity: an ex vivo study in patients with inflammatory bowel disease. Aliment. Pharmacol. Ther. 2005; 21: 1105-1109.
de Boer NK, Wong DR, Jharap B et al. Dose-dependent influence of 5-aminosalicylates on thiopurine metabolism. Am. J. Gastroenterol. 2007; 102: 2747-2753.
de Graaf P, de Boer NK, Wong DR et al. Influence of 5-aminosalicylic acid on 6-thioguanosine phosphate metabolite levels: a prospective study in patients under steady thiopurine therapy. Br. J. Pharmacol. 2010; 160: 1083-1091.
Takahashi K, Bamba S, Morita Y et al. pH-dependent 5-aminosalicylates releasing preparations do not affect thiopurine metabolism. Digestion 2019; 100: 238-246.
Komiyama T, Yajima T, Kubota R et al. Lower doses of 6-mercaptopurine/azathioprine bring enough clinical efficacy and therapeutic concentration of erythrocyte 6-mercaptopurine metabolite in Japanese IBD patients. J. Crohns Colitis 2008; 2: 315-321.
Neurath MF, Kiesslich R, Teichgräber U et al. 6-Thioguanosine diphosphate and triphosphate levels in red blood cells and response to azathioprine therapy in Crohn's disease. Clin. Gastroenterol. Hepatol. 2005; 3: 1007-1014.
Dujardin RW, Meijer B, de Boer NK, D'Haens GR, Lowenberg M. Usefulness of mean corpuscular volume as a surrogate marker for monitoring thiopurine treatment in inflammatory bowel disease. Eur. J. Gastroenterol. Hepatol. 2016; 28: 991-996.
Olaisen M, Spigset O, Flatberg A et al. Mucosal 5-aminosalicylic acid concentration, drug formulation and mucosal microbiome in patients with quiescent ulcerative colitis. Aliment. Pharmacol. Ther. 2019; 49: 1301-1313.
Gearry RB, Barclay ML. Azathioprine and 6-mercaptopurine pharmacogenetics and metabolite monitoring in inflammatory bowel disease. J. Gastroenterol. Hepatol. 2005; 20: 1149-1157.
Kumagai K, Hiyama K, Ishioka S et al. Allelotype frequency of the thiopurine methyltransferase (TPMT) gene in Japanese. Pharmacogenetics 2001; 11: 275-278.
Yang SK, Hong M, Baek J et al. A common missense variant in NUDT15 confers susceptibility to thiopurine-induced leukopenia. Nat. Genet. 2014; 46: 1017-1020.
Milosevic G, Kotur N, Krstovski N et al. Variants in TPMT, ITPA, ABCC4 and ABCB1 genes as predictors of 6-mercaptopurine induced toxicity in children with acute lymphoblastic leukemia. J. Med. Biochem. 2018; 37: 320-327.
Takatsu N, Matsui T, Murakami Y et al. Adverse reactions to azathioprine cannot be predicted by thiopurine S-methyltransferase genotype in Japanese patients with inflammatory bowel disease. J. Gastroenterol. Hepatol. 2009; 24: 1258-1264.
Ban H, Andoh A, Tanaka A et al. Analysis of thiopurine S-methyltransferase genotypes in Japanese patients with inflammatory bowel disease. Intern. Med. 2008; 47: 1645-1648.
Brunner M, Assandri R, Kletter K et al. Gastrointestinal transit and 5-ASA release from a new mesalazine extended-release formulation. Aliment. Pharmacol. Ther. 2003; 17: 395-402.