Impact of Chronotherapy on 6-Mercaptopurine Metabolites in Inflammatory Bowel Disease: A Pilot Crossover Trial.
Impact of Chronotherapy on 6-Mercaptopurine Metabolites in Inflammatory Bowel Disease: A Pilot Crossover Trial.
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DOI：
10.14309/ctg.0000000000000549
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发表时间：
2023-02-01
影响因子：
3.6
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中科院分区：
文献类型：
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时间疗法是根据宿主的生物节律选择药物治疗的时间，以优化药物疗效并将毒性降至最低。硫唑嘌呤/6-巯基嘌呤（AZA/6-MP）的疗效和骨髓抑制与代谢产物6-硫鸟嘌呤相关，而代谢产物6-甲巯基嘌呤与肝毒性相关。这是一项为期10周的单中心前瞻性交叉试验，涉及26名接受稳定剂量和时间的AZA或6-MP治疗的非活动性炎症性肠病（IBD）患者。参与者被转换到相反的分娩时间（早晨或晚上），持续10周，并在两个时间点进行代谢物测量。早晨与晚上给药时，6-硫鸟嘌呤水平分别为225.7 ± 155.1 vs 175.0 ± 106.9 6-甲巯基嘌呤分别为825.1 ± 1023.3和2395.3 ± 2880.3（P < 0.01）（P < 0.01），69%（18/26）的参与者在早上有更好的代谢产物。早晨服用最佳剂量的参与者通过校正睡眠中点具有较早的时钟型。在第一项关于时间疗法在IBD中的潜在作用的研究中，我们发现（i）AZA或6-MP的早晨给药导致更佳的代谢产物谱，（ii）宿主时间型可以帮助确定三分之一的患者将从晚上给药中受益。肝脏中AZA/6-MP活性代谢酶的昼夜节律调节可能是这些差异的原因。这项初步研究证实了在未来的IBD疾病多中心临床试验中纳入时间疗法的必要性。
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. 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. 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. 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.