Low‐dose azathioprine or mercaptopurine in combination with allopurinol can bypass many adverse drug reactions in patients with inflammatory bowel disease

@article{Ansari2010LowdoseAO,
  title={Low‐dose azathioprine or mercaptopurine in combination with allopurinol can bypass many adverse drug reactions in patients with inflammatory bowel disease},
  author={Azhar R. Ansari and Nisha Patel and Jeremy D. Sanderson and J O'donohue and John A. Duley and Timothy H. Florin},
  journal={Alimentary Pharmacology \& Therapeutics},
  year={2010},
  volume={31}
}
Aliment Pharmacol Ther 31, 640–647 
Real‐life study of safety of thiopurine‐allopurinol combination therapy in inflammatory bowel disease: myelotoxicity and hepatotoxicity rarely affect maintenance treatment
Low‐dose thiopurine‐allopurinol (LDTA) combination therapy is a commonly applied optimisation strategy in IBD patients with a skewed thiopurine metabolism.
Early prediction of thiopurine‐induced hepatotoxicity in inflammatory bowel disease
Hepatotoxicity, gastrointestinal complaints and general malaise are common limiting adverse reactions of azathioprine and mercaptopurine in IBD patients, often related to high steady‐state
Letter: allopurinol co‐therapy is safe and effective in autoimmune hepatitis
Al-Shamma, S McCrudden, R McLaughlin, S Letter England Aliment Pharmacol Ther. 2013 May;37(9):919. doi: 10.1111/apt.12285.
Review article: opportunities to improve and expand thiopurine therapy for autoimmune hepatitis
  • A. Czaja
  • Medicine
    Alimentary pharmacology & therapeutics
  • 2020
Thiopurines in combination with glucocorticoids are used as first‐line, second‐line and maintenance therapies in autoimmune hepatitis and opportunities exist to improve and expand their use.
Randomised clinical trial: efficacy, safety and dosage of adjunctive allopurinol in azathioprine/mercaptopurine nonresponders (AAA Study)
TLDR
Allopurinol reverses hypermethylation towards 6‐methylmercaptopurine (6MMP) instead of 6‐thioguanine nucleotides (6TGN) which is associated with inefficacy in patients with IBD.
Interindividual differences in thiopurine metabolism : studies with focus on inflammatory bowel disease
The thiopurines, 6-mercaptopurine and its prodrug azathioprine, are used in the treatment of inflammatory bowel disease, ulcerative colitis and Crohn´s disease. The main active metabolites are the ...
Review article: the benefits of pharmacogenetics for improving thiopurine therapy in inflammatory bowel disease
Aliment Pharmacol Ther 2012; 35: 15–36
Review article: recent advances in pharmacogenetics and pharmacokinetics for safe and effective thiopurine therapy in inflammatory bowel disease
Azathioprine and mercaptopurine have a pivotal role in the treatment of inflammatory bowel disease (IBD). However, because of their complex metabolism and potential toxicities, optimal use of
Randomised clinical trial: individualised vs. weight‐based dosing of azathioprine in Crohn's disease
Azathioprine (AZA), a pro‐drug metabolised to the active metabolites 6‐tioguanine nucleotides (6TGN), is a steroid‐sparing therapy for Crohn's disease (CD).
Review article: the role of non‐biological drugs in refractory inflammatory bowel disease
TLDR
A small number of patients with inflammatory bowel disease do not respond to, or are intolerant of conventional immunosuppressive drugs, and biological agents are alternative treatments, which may not be suitable or available to some patients.
...
...

References

SHOWING 1-10 OF 38 REFERENCES
Tolerability and safety of mercaptopurine in azathioprine‐intolerant patients with inflammatory bowel disease
TLDR
The successful use of mercaptopurine is described, but data to support this strategy are needed.
Prospective evaluation of the pharmacogenetics of azathioprine in the treatment of inflammatory bowel disease
TLDR
A small number of patients with inflammatory bowel disease receiving azathioprine withdraw treatment due to side effects or lack of clinical response to AZA, and this data indicates that this may be a cause for concern.
Allopurinol safely and effectively optimizes tioguanine metabolites in inflammatory bowel disease patients not responding to azathioprine and mercaptopurine
Background : Many non‐responders to azathioprine or mercaptopurine (6‐mercaptopurine) have high normal thiopurine methyltransferase activity and preferentially metabolize mercaptopurine to produce
Long‐term outcome of using allopurinol co‐therapy as a strategy for overcoming thiopurine hepatotoxicity in treating inflammatory bowel disease
TLDR
It is demonstrated that allopurinol with AZA/ciclosporin/steroid ‘triple therapy’ improved renal graft survival and Hepatotoxicity results in the withdrawal of thiopurines drugs, azathioprine (AZA) and mercaptopurine (MP).
Thiopurine methyltransferase activity and the use of azathioprine in inflammatory bowel disease
TLDR
Patients with thiopurine methyltransferase (TPMT) deficiency are intolerant to azathioprine, whilst carriers are at increased risk of side‐effects.
Adverse events leading to modification of therapy in a large cohort of patients with inflammatory bowel disease
Adverse events leading to discontinuation or dose reduction of thiopurine therapy occur in 9–28% of patients with inflammatory bowel disease.
The purine path to chemotherapy
  • G. Elion
  • Medicine
    In Vitro Cellular & Developmental Biology
  • 2007
TLDR
Research on antimetabolites of nucleic acid purines led to drugs for the treatment of acute leukemia, gout and hyperuricemia, and herpesvirus infections, and for the prevention of organ transplant rejection.
Influence of xanthine oxidase on thiopurine metabolism in Crohn’s disease
TLDR
Thiopurines, azathioprine and mercaptopurine are extensively used in Crohn’s disease and can be diverted by either thiopurine methyltransferase (TPMT), or by xanthine oxidase/dehydrogenase (XOD) which forms 6‐thiouric acid (6TU).
Initial clinical experience with allopurinol‐thiopurine combination therapy in pediatric inflammatory bowel disease
TLDR
Combination therapy successfully shunted thiopurine metabolites to a more favorable pattern in pediatric IBD patients, and reversible neutropenia was the most common side effect.
...
...