INTRODUCTION
tissue injury of the intestinal mucosa, ulcerative colitis, toxicity, UC, Crohn's disease, IBD
INFLAMMATORY BOWEL DISEASE, ULCERATIVE COLITIS, REMISSION, CROHN'S DISEASE, CHRONIC INFLAMMATION
Inflammatory bowel disease (IBD), which includes both Crohn's disease (CD) and ulcerative colitis (UC), affects 1–1.3 million people in the United States and is characterized by chronic inflammation and tissue injury of the intestinal mucosa as a consequence of inappropriate and exaggerated immune response to intestinal microbiota (The most commonly used immunomodulators in IBD are the thiopurines, 6-mercaptopurine (6-MP), and its prodrug, azathioprine (AZA). Clinical studies support that AZA/6-MP is effective for promoting both induction and maintenance of remission in IBD (A new alternative approach to manipulate the 6-MP metabolism pathway is to leverage the circadian oscillation of drug metabolism pathways through time-of-day dependent dosage (“chronotherapy”). A central clock in the suprachiasmatic nucleus regulates behavioral and physiological function throughout the body in tune with the environment. The suprachiasmatic nucleus acts as a master clock that integrates environmental signals (primary light) and coordinates the activity of peripheral clocks. This leads to time-dependent responses such as the release of certain hormones, including melatonin and cortisol, which regulate proinflammatory cytokine expression and leukocyte functions, as well as oscillation in activities of enzymes that are involved in the generation of active or toxic forms of medications (Chronotherapy is the timing of medical interventions according to the host's biological rhythms to optimize drug efficacy and minimize toxicity (However, to the best of our knowledge, chronotherapy in IBD has not been studied. To fill this knowledge gap, we aimed to determine whether chronotherapy improves therapeutic drug levels in IBD. In this regard, we chose to focus on timing of AZA and 6-MP delivery because (i) the drug metabolism is well-characterized; (ii) the metabolites associated with efficacy and toxicity are well known; (iii) long-term clinical studies have been conducted that show therapeutic response and toxicity correlation with 6-TG and 6-MMP levels, respectively; and (iv) patients are maintained on once daily stable dosage of AZA or 6-MP for extended periods. Therefore, the goal of this study was to determine the chronotherapy of AZA and 6-MP in IBD that resulted in optimal metabolite levels.