Inflammatory bowel disease 6-mercaptopurine

Dubinsky, M. C. (2004) Azathioprine, 6-mercaptopurine in inflammatory bowel disease pharmacology, efficacy, and safety. Clin. Gastroenterol. Hepatol. 2, 731-743. 

Su, C., and Lichtenstein, G. R. (2004) Treatment of inflammatory bowel disease with azathro-prine and 6-mercaptopurine. Gastroenterol. Clin. North Am. 33, 209-234. 

Therapeutic pyramid approach to inflammatory bowel diseases. Treatment choice is predicated on both the severity of the illness and the responsiveness to therapy. Agents at the bottom of the pyramid are less efficacious but carry a lower risk of serious adverse effects. Drugs may be used alone or in various combinations. Patients with mild disease may be treated with 5-aminosalicylates (with ulcerative colitis or Crohn s colitis), topical corticosteroids (ulcerative colitis), antibiotics (Crohn s colitis or Crohn s perianal disease), or budesonide (Crohn s ileitis). Patients with moderate disease or patients who fail initial therapy for mild disease may be treated with oral corticosteroids to promote disease remission immunomodulators (azathioprine, mercaptopurine, methotrexate) to promote or maintain disease remission or anti-TNF antibodies. Patients with moderate disease who fail other therapies or patients with severe disease may require intravenous corticosteroids, anti-TNF antibodies, or surgery. Natalizumab is reserved for patients with severe Crohn s disease who have failed immunomodulators and TNF antagonists. Cyclosporine is used primarily for patients with severe ulcerative colitis who have failed a course of intravenous corticosteroids. TNF, tumor necrosis factor. 

In a retrospective study, postoperative infectious complications were evaluated in 159 patients with inflammatory bowel disease undergoing elective surgery (317). Immunosuppression consisted of glucocorticoid monotherapy (n = 56), a glucocorticoid + azathioprine or mercaptopurine (n — 52), and neither a glucocorticoid nor azathioprine or mercaptopurine (n — 51). The adjusted odds ratios for any infection and major infections in patients who took glucocorticoid were 3.69 and 5.54 respectively, and in patients who took azathioprine or mercaptopurine 1.68 and 1.20. Thus, preoperative use of glucocorticoid in patients with inflammatory bowel disease increased the risk of postoperative infectious complications. 

Azathioprine and 6-mercaptopurine have a serum half-life of less than 2 hours however, the active metabolites, 6-thioguanine nucleotides, are concentrated in cells resulting in a prolonged half-life of days. The prolonged kinetics of 6-thioguanine nucleotide results in a median delay of 17 weeks before onset of therapeutic benefit from oral azathioprine or 6-mercaptopurine is observed in patients with inflammatory bowel disease. 

Nielsen OH, Vainer B, Rask-Madsen J. Review article the treatment of inflammatory bowel disease with 6-mercaptopurine or azathioprine. Aliment Pharmacol Ther 2001 15 1699-1708. 

Azathioprine, a prodrug converted to 6-mercaptopurine, is widely used as a post-transplant immunosuppressant and in various autoimmune or chronic inflammatory disorders, such as rheumatoid arthritis, dermatomyositis, systemic lupus eiythematosus, skin diseases, and inflammatory bowel diseases. 

Experience in children with juvenile chronic arthritis or chronic inflammatory bowel disease has also accumulated, and the toxicity profile of azathioprine or mercaptopurine appears to be very similar to that previously found in the adult population (SEDA-21, 381) (SEDA-22, 410). 

Pancreatitis due to azathioprine or mercaptopurine has usually been reported as part of the hypersensitivity syndrome (SEDA-16,520) (SEDA-20,341). It has mostly been observed in patients with inflammatory bowel disease, and required withdrawal of treatment in 1.3% of patients with Crohn s disease (3). Pancreatitis was not dose-related within the therapeutic range of doses and often recurred in patients who were rechallenged with either drug (SEDA-20, 341) (35). Fatal hemorrhagic pancreatitis occurred in one patient, but a role of concomitant drugs was also possible (SEDA-20, 341). Pancreatitis or hyperamylasemia were not significantly different in renal transplant patients randomly assigned to receive azathioprine or ciclosporin, and other causative factors were found in most patients with pancreatitis (36). 

Sandborn WJ. A review of immune modifier therapy for inflammatory bowel disease azathioprine, 6-mercaptopurine, cyclosporine, and methotrexate. Am J Gastroenterol 1996 91(3) 423-33. 

Present DH, Meltzer SJ, Krumholz MP, Wolke A, Korelitz BI. 6-Mercaptopurine in the management of inflammatory bowel disease short- and long-term toxicity. Ann Intern Med 1989 lll(8) 641-9. 

Korelitz BI, Zlatanic J, Goel F, Fuller S. Allergic reactions to 6-mercaptopurine during treatment of inflammatory bowel disease. J Clin Gastroenterol 1999 28(4) 341. ... 

Korelitz BI, Fuller SR, Warman JI, Goldberg MD. Shingles during the course of treatment with 6-mercaptopurine for inflammatory bowel disease. Am J Gastroenterol 1999 94(2) 424-6. 

Korelitz BI, Mirsky FJ, Fleisher MR, Warman JI, Wisch N, Gleim GW. Malignant neoplasms subsequent to treatment of inflammatory bowel disease with 6-mercaptopurine. Am J Gastroenterol 1999 94(ll) 3248-53. 

Dubinsky MC, Lamoflie S, Yang HY, et al. Pharmacogenomics and metaboUte measurement for 6-mercaptopurine flier y in inflammatory bowel disease. Gastroenterology 2000 18 705-713. 

Haber CJ, Meltzer SJ, Present DH, etal. Nature and course of pancreatitis caused by 6-mercaptopurine in the treatment of inflammatory bowel disease. Gastroenterology 1986 91 982-986. 

An interesting example of a DDI due to the inhibition of a non-CYP enzyme that can have serious clinical consequences is the inhibition of xanthine oxidase by allopu-rinol 6-mercaptopurine (6-MP) as an antimetabolite type of antineoplastic drug. One of its indications is in the treatment of inflammatory bowel disease. Actually, 6-MP is a prodrug whose active metabolite, 6-thiogua-nine (6-TG) is responsible for its therapeutic activity. Some nonresponders to 6-MP do not form sufficient amounts of 6-TG. A complementary pathway of 6-MP metabolism is oxidation to 6-thiouric acid (6TU), which is mediated by xanthine oxidase. Inhibition of this complementary pathway by allopurinol shunts the metabolism of 6-MP favoring increased formation of 6-TG. 

Sparrow, M., Hande, S., Friedman, S., Lim, W., Reddy, S., Cao, D., et al. (2005). Allopurinol safely and effectively optimizes tiogua-nine metabolites in inflammatory bowel disease patients not responding to azathiopurine and mercaptopurine. Alimentary Pharmacology Cf Therapeutics, 22, 441—446. 

Gearry R B, Barclay M L (2005). Azathioprine and 6-mercaptopurine pharmacogenetics and metabolite monitoring in inflammatory bowel disease. Gastroenterol. Hepatol. 20 1149-1157. 

The doses of mercaptopurine or azathioprine needed to maintain remission in Japanese children with inflammatory bowel disease are lower than those reported in... 

Ansari A, Patel N, Sanderson J, O Donohue J, Duley JA, Florin TH. Low-dose azathioprine or mercaptopurine in combination with allopurinol can bypass many adverse drug reactions in patients with inflammatory bowel disease. Aliment Pharmacol Ther 2010 31(6) 640-7. 

In 22 patients with inflammatory bowel disease who had adverse reactions to azathioprine, mercaptopurine was tolerated for longer (median 219, range 3-503 days) than azathioprine (median 14, range 2-180 days) [112 ]. The adverse reactions to azathioprine were nausea and vomiting (n = 14), flu-like symptoms (n = 5), myalgia/arthral-gia (n = 6), headaches (n = 6), and diarrhea (n = 2). 

Hypersensitivity reactions In 21 patients with inflammatory bowel disease who had hypersensitivity reactions to azathioprine or mercaptopurine within 6 weeks, thioguanine 10-40 mg/day elicited hypersensitivity reactions in only four, after a median of 9 days pancreatitis did not recur [1185]. 

Hindorf U, Johansson M, Eriksson A, Kvifors E, Aimer SH. Mercaptopurine treatment should be considered in azathioprine intolerant patients with inflammatory bowel disease. Aliment Pharmacol Ther 2009 29(6) 654-61. 

Derijks LJ, de Jong DJ, Gilissen LP, Engels LG, Hooymans PM, Jansen JB, Mulder CJ. 6-Thioguanine seems promising in azathioprine- or 6-mercaptopurine-intol-erant inflammatory bowel disease patients a short-term safety assessment. Eur J Gastroenterol Hepatol 2003 15(1) 63-7. 

Domenech E, Nos P, Papo M, Lopez-San Romin A, Garcia-Planella E, Gassull MA. 6-mercaptopurine in patients with inflammatory bowel disease and previous digestive intolerance of azathioprine. Scand J Gastroenterol 2005 40(1) 52-5. 

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