Center for Integrated Microbiome and Chronobiology Research, Rush University Medical Center, Chicago, Illinois, USA.
Rush University Medical Center, Department of Internal Medicine, Section of Digestive Diseases, Chicago, Illinois, USA.
Clin Transl Gastroenterol. 2023 Feb 1;14(2):e00549. doi: 10.14309/ctg.0000000000000549.
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.
时间治疗学是根据宿主的生物节律来调整药物的时间，以优化药物疗效并最小化毒性。硫唑嘌呤/6-巯基嘌呤（AZA/6-MP）的疗效和骨髓抑制与代谢物 6-硫鸟嘌呤有关，而代谢物 6-甲基巯基嘌呤与肝毒性有关。
这是一项单中心、10 周前瞻性交叉试验，涉及 26 名处于缓解期的炎症性肠病（IBD）患者，他们正在稳定剂量和时间接受 AZA 或 6-MP 治疗。参与者将在 10 周内切换到相反的给药时间（早晨或晚上），并在两个时间点测量代谢物。
与晚上给药相比，早晨给药时 6-硫鸟嘌呤水平为 225.7±155.1 对 175.0±106.9（P＜0.01），6-甲基巯基嘌呤水平为 825.1±1023.3 对 2395.3±2880.3（P＜0.01），26 名参与者中有 69%（18 名）在早晨的代谢物谱更好。在早晨有最佳剂量的参与者通过校正睡眠中点，表现出更早的生物钟类型。
在关于时间治疗学在 IBD 中潜在作用的第一项研究中，我们发现（i）AZA 或 6-MP 的早晨给药导致更优化的代谢物谱，（ii）宿主生物钟类型可以帮助识别三分之一将从晚上给药中受益的患者。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。这项初步研究证实需要将时间治疗学纳入未来的 IBD 疾病多中心临床试验。
