BACKGROUND: 6-Mercaptopurine and its prodrug azathioprine are effective medications for refractory inflammatory bowel disease. However, use of these drugs has been limited by concerns about their toxicity. Colonic delivery of azathioprine may reduce its systemic bioavailability and limit toxicity. AIM: To determine the bioavailability of 6-mercaptopurine after administration of azathioprine via three colonic delivery formulations. METHODS: Twenty four healthy human subjects each received 50 mg of azathioprine by one of four delivery formulations (each n = 6): oral; delayed release oral; hydrophobic rectal foam; and hydrophilic rectal foam. All subjects also received a 50 mg dose of intravenous azathioprine during a separate study period. Plasma concentrations of 6-mercaptopurine were determined by high pressure liquid chromatography. RESULTS: The bioavailabilities of 6-mercaptopurine after colonic azathioprine administration via delayed release oral, hydrophobic rectal foam, and hydrophilic rectal foam (7%, 5%, 1%; respectively) were significantly lower than the bioavailability of 6-mercaptopurine after oral azathioprine administration (47%) by Wilcoxon rank sum pairwise comparison. CONCLUSIONS: Azathioprine delivered to the colon by delayed release oral and rectal foam formulations considerably reduced systemic 6-mercaptopurine bioavailability. The therapeutic potential of these colonic delivery methods, which can potentially limit toxicity by local delivery of high doses of azathioprine, should be investigated in patients with inflammatory bowel disease.
BACKGROUND:6-Mercaptopurine and its prodrug azathioprine are effective medications for refractory inflammatory bowel disease. However, use of these drugs has been limited by concerns about their toxicity. Colonic delivery of azathioprine may reduce its systemic bioavailability and limit toxicity. AIM: To determine the bioavailability of 6-mercaptopurine after administration of azathioprine via three colonic delivery formulations. METHODS: Twenty four healthy human subjects each received 50 mg of azathioprine by one of four delivery formulations (each n = 6): oral; delayed release oral; hydrophobic rectal foam; and hydrophilic rectal foam. All subjects also received a 50 mg dose of intravenous azathioprine during a separate study period. Plasma concentrations of 6-mercaptopurine were determined by high pressure liquid chromatography. RESULTS: The bioavailabilities of 6-mercaptopurine after colonic azathioprine administration via delayed release oral, hydrophobic rectal foam, and hydrophilic rectal foam (7%, 5%, 1%; respectively) were significantly lower than the bioavailability of 6-mercaptopurine after oral azathioprine administration (47%) by Wilcoxon rank sum pairwise comparison. CONCLUSIONS:Azathioprine delivered to the colon by delayed release oral and rectal foam formulations considerably reduced systemic 6-mercaptopurine bioavailability. The therapeutic potential of these colonic delivery methods, which can potentially limit toxicity by local delivery of high doses of azathioprine, should be investigated in patients with inflammatory bowel disease.
Authors: Virginia L Priest; Evan J Begg; Sharon J Gardiner; Christopher M A Frampton; Richard B Gearry; Murray L Barclay; David W J Clark; Paul Hansen Journal: Pharmacoeconomics Date: 2006 Impact factor: 4.981
Authors: Xiaoyan Yang; Catherine M T Sherwin; Tian Yu; Venkata K Yellepeddi; Hermine I Brunner; Alexander A Vinks Journal: Expert Rev Clin Pharmacol Date: 2015-07-09 Impact factor: 5.045
Authors: Imke Tiede; Gerhard Fritz; Susanne Strand; Daniela Poppe; Radovan Dvorsky; Dennis Strand; Hans Anton Lehr; Stefan Wirtz; Christoph Becker; Raja Atreya; Jonas Mudter; Kai Hildner; Brigitte Bartsch; Martin Holtmann; Richard Blumberg; Henning Walczak; Heiko Iven; Peter R Galle; Mohammad Reza Ahmadian; Markus F Neurath Journal: J Clin Invest Date: 2003-04 Impact factor: 14.808