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Impact of Chronotherapy on 6-Mercaptopurine Metabolites in Inflammatory Bowel Disease: A Pilot Crossover Trial

Chronotherapy is the timing of medication according to biological rhythms of the host to optimize drug efficacy and minimize toxicity. Efficacy and myelosuppression of azathioprine/6-mercaptopurine (AZA/6-MP) are correlated with the metabolite 6-thioguanine, while the metabolite 6-methylmercaptopuri...

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Autores principales: Swanson, Garth R., Biglin, Mary, Raff, Hannah, Chouhan, Vijit, Jochum, Sarah, Shaikh, Maliha, Francey, Lauren, Bishehsari, Faraz, Hogenesch, John, Keshavarzian, Ali
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Wolters Kluwer 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9945554/
https://www.ncbi.nlm.nih.gov/pubmed/36730289
http://dx.doi.org/10.14309/ctg.0000000000000549
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author Swanson, Garth R.
Biglin, Mary
Raff, Hannah
Chouhan, Vijit
Jochum, Sarah
Shaikh, Maliha
Francey, Lauren
Bishehsari, Faraz
Hogenesch, John
Keshavarzian, Ali
author_facet Swanson, Garth R.
Biglin, Mary
Raff, Hannah
Chouhan, Vijit
Jochum, Sarah
Shaikh, Maliha
Francey, Lauren
Bishehsari, Faraz
Hogenesch, John
Keshavarzian, Ali
author_sort Swanson, Garth R.
collection PubMed
description Chronotherapy is the timing of medication according to biological rhythms of the host to optimize drug efficacy and minimize toxicity. Efficacy and myelosuppression of azathioprine/6-mercaptopurine (AZA/6-MP) are correlated with the metabolite 6-thioguanine, while the metabolite 6-methylmercaptopurine correlates with hepatotoxicity. METHODS: This was a single-center, 10-week prospective crossover trial involving 26 participants with inactive inflammatory bowel disease (IBD) on a stable dose and time of AZA or 6-MP therapy. Participants were switched to the opposite delivery time (morning or evening) for 10 weeks, and metabolite measurements were at both time points. RESULTS: In the morning vs evening dosing, 6-thioguanine levels were 225.7 ± 155.1 vs 175.0 ± 106.9 (P < 0.01), and 6-methylmercaptopurine levels were 825.1 ± 1,023.3 vs 2,395.3 ± 2,880.3 (P < 0.01), with 69% (18 out of 26) of participants had better metabolite profiles in the morning. Participants with optimal dosing in the morning had an earlier chronotype by corrected midpoint of sleep. DISCUSSION: In the first study on a potential role of chronotherapy in IBD, we found (i) morning dosing of AZA or 6-MP resulted in more optimal metabolite profiles and (ii) host chronotype could help identify one-third of patients who would benefit from evening dosing. Circadian regulation of metabolic enzymes of AZA/6-MP activity in the liver is the likely cause of these differences. This pilot study confirms the need to incorporate chronotherapy in future multicenter clinical trials on IBD disease.
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spelling pubmed-99455542023-02-23 Impact of Chronotherapy on 6-Mercaptopurine Metabolites in Inflammatory Bowel Disease: A Pilot Crossover Trial Swanson, Garth R. Biglin, Mary Raff, Hannah Chouhan, Vijit Jochum, Sarah Shaikh, Maliha Francey, Lauren Bishehsari, Faraz Hogenesch, John Keshavarzian, Ali Clin Transl Gastroenterol Article Chronotherapy is the timing of medication according to biological rhythms of the host to optimize drug efficacy and minimize toxicity. Efficacy and myelosuppression of azathioprine/6-mercaptopurine (AZA/6-MP) are correlated with the metabolite 6-thioguanine, while the metabolite 6-methylmercaptopurine correlates with hepatotoxicity. METHODS: This was a single-center, 10-week prospective crossover trial involving 26 participants with inactive inflammatory bowel disease (IBD) on a stable dose and time of AZA or 6-MP therapy. Participants were switched to the opposite delivery time (morning or evening) for 10 weeks, and metabolite measurements were at both time points. RESULTS: In the morning vs evening dosing, 6-thioguanine levels were 225.7 ± 155.1 vs 175.0 ± 106.9 (P < 0.01), and 6-methylmercaptopurine levels were 825.1 ± 1,023.3 vs 2,395.3 ± 2,880.3 (P < 0.01), with 69% (18 out of 26) of participants had better metabolite profiles in the morning. Participants with optimal dosing in the morning had an earlier chronotype by corrected midpoint of sleep. DISCUSSION: In the first study on a potential role of chronotherapy in IBD, we found (i) morning dosing of AZA or 6-MP resulted in more optimal metabolite profiles and (ii) host chronotype could help identify one-third of patients who would benefit from evening dosing. Circadian regulation of metabolic enzymes of AZA/6-MP activity in the liver is the likely cause of these differences. This pilot study confirms the need to incorporate chronotherapy in future multicenter clinical trials on IBD disease. Wolters Kluwer 2022-11-22 /pmc/articles/PMC9945554/ /pubmed/36730289 http://dx.doi.org/10.14309/ctg.0000000000000549 Text en © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY) (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Article
Swanson, Garth R.
Biglin, Mary
Raff, Hannah
Chouhan, Vijit
Jochum, Sarah
Shaikh, Maliha
Francey, Lauren
Bishehsari, Faraz
Hogenesch, John
Keshavarzian, Ali
Impact of Chronotherapy on 6-Mercaptopurine Metabolites in Inflammatory Bowel Disease: A Pilot Crossover Trial
title Impact of Chronotherapy on 6-Mercaptopurine Metabolites in Inflammatory Bowel Disease: A Pilot Crossover Trial
title_full Impact of Chronotherapy on 6-Mercaptopurine Metabolites in Inflammatory Bowel Disease: A Pilot Crossover Trial
title_fullStr Impact of Chronotherapy on 6-Mercaptopurine Metabolites in Inflammatory Bowel Disease: A Pilot Crossover Trial
title_full_unstemmed Impact of Chronotherapy on 6-Mercaptopurine Metabolites in Inflammatory Bowel Disease: A Pilot Crossover Trial
title_short Impact of Chronotherapy on 6-Mercaptopurine Metabolites in Inflammatory Bowel Disease: A Pilot Crossover Trial
title_sort impact of chronotherapy on 6-mercaptopurine metabolites in inflammatory bowel disease: a pilot crossover trial
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9945554/
https://www.ncbi.nlm.nih.gov/pubmed/36730289
http://dx.doi.org/10.14309/ctg.0000000000000549
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