Although most patients have an excellent response to standard therapy (azathioprine in combination with corticosteroids), approximately 10%-15% have intolerance or an insufficient response to azathioprine treatment
JAMA 1964; 188:802-806 3
Recent reports suggest 6-thioguanine nucleotide (6-TGN) levels (>235) independently correlate with remission
The proposed therapeutic threshold level of the active 6-thioguanine nucleotides (6-TGN) is ≥ 235 pmol/8 × 10 8 erythrocytes
Thiopurines (mercaptopurine, azathioprine and thioguanine) are well-established maintenance treatments for a wide range of diseases such as leukemia, inflammatory bowel disease (IBD), systemic lupus erythematosus (SLE) and other inflammatory and autoimmune diseases in general
This activity will highlight the mechanism of Thiopurines are often the mainstay of treatment for many patients with inflammatory bowel disease
Thiopurines (azathioprine and mercaptopurine) are one of the immunosuppressive mainstays for the treatment of inflammatory bowel disease
Acute lymphoblastic leukemia (ALL) is the most common cancer in children and includes a prolonged maintenance phase of therapy which has significantly decreased the risk of relapse (1, 2)
The oral form of azathioprine is quickly and nonenzymatically cleaved to 6-MP
6-MP is well-tolerated by a Thiopurines (ie, azathioprine [AZA] and mercaptopurine, also known as 6-mercaptopurine, [6-MP]) exert a glucocorticoid-sparing effect for patients with inflammatory bowel disease (IBD) who cannot maintain remission when glucocorticoids are tapered and withdrawn
Mercaptopurine is then converted into thioguanine nucleotides Glutathione-mediated thiolysis of azathioprine in the liver is believed to be the main mechanism for the conversion of this drug to 6-mercaptopurine
3 Hepatotoxicity can also include anorexia and diarrhea
The thiopurines azathioprine (AZA) and 6-mercaptopurine (6-MP) are immunosuppressive drugs widely used for the treatment of IBD that have demonstrated efficacy in the induction and maintenance of These drugs can be taken long term
7 However, when using azathioprine with allopurinol, a lower dose of azathioprine (about 25%-50% of the monotherapy Mild forms of toxic hepatitis may not cause any symptoms and may be detected only by blood tests
Alternatively, 2 competitive catabolic pathways for 6-MP also exist; the conversion into 6-thiouric acid by xanthine oxidase (XO) or into hepatotoxic 6-methylmercaptopurine (6-MMP) via thiopurine methyltransferase (TPMT)
Azathioprine is a prodrug that is metabolized to 6-MP and then further metabolized to 6-TGs and 6-MMP
Azathioprine and 6-mercaptopurine are thiopurines, and azathioprine is an imidazolyl derivative of 6-mercaptopurine
It is also used an immunosuppressant in the treatment of Crohn's disease and ulcerative colitis
Azathioprine (AZA) is an immunosuppressive agent that acts through its effects as an antagonist of purine metabolism, resulting in the inhibition of deoxyribonucleic acid (DNA), ribonucleic acid (RNA), and protein synthesis
METHODS: 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
6-MP undergoes two major inactivation routes (Figure 1)
6-MP is subsequently metabolized through several steps to a group of compounds called 6-TG
Thioguanine therapy is associated with minor, usually transient and asymptomatic elevations in serum aminotransferase levels and has also been linked to rare instances of cholestatic acute liver injury and to chronic liver injury Azathioprine, a prodrug of 6-mercaptopurine, is metabolised to 6-MMPN and 6-TGN
Azathioprine is converted to 6MP in the presence of glutathione transferases or other sulfhydryl-containing Azathioprine- maximum dose of 2
Azathioprine is first converted _in vivo_ to mercaptopurine in the liver
Azathioprine, a widely prescribed immunosuppressant, has been associated with different forms of hepatotoxicity
The present study aims to investigate whether clinically relevant concentrations (1 and 5 μM) and a supra-pharmacological concentration (25 μM) of AZA
Gross's comments on our subject review and his recommendations for monitoring for hepatotoxicity during treatment of Crohn's disease with 6
AZA is the pro-drug and is metabolized to 6-MP in the liver by the enzyme glutathione-S-transferase (GST)
You start the patient on prednisone 60 mg a day, and the patient’s liver enzymes start improving
The Mater Hospital is hiring Staff Nurses for National Centre of Inherited Metabolic Disorders (NCIMD)
Introduction
The activities of XO, HGPRT, and TPMT determine the efficacy and toxicity of azathioprine and its metabolites [127 To answer this question, it is first important to understand the metabolic pathway of azathioprine
5 years in combination
Once thiopurine therapy has been undertaken and an equilibrated drug level is Azathioprine is an antimetabolite thiopurine analogue drug that interferes with DNA synthesis and suppresses the immune system response
1 – 3 Additionally, they have shown efficacy in perianal fistulizing Crohn's disease and Abstract
Recent reports suggest 6-thioguanine nucleotide (6-TGN) levels (>235) independently correlate with remission
3 Hepatotoxicity can also include anorexia and diarrhea
Some patients on azathioprine or mercaptopurine exhibit preferential 6-MMP production, having a 6-MMP/6-TGN ratio >20; this has also been termed “metabolic shunting
Long term use requires periodic bloodwork and evaluation by your doctor
7 However, when using azathioprine with allopurinol, a lower dose of azathioprine (about 25%–50% of
AZA and 6MP are well absorbed, but with a high first-pass metabolism, their bioavailability is low at about 15 %
Use Caution/Monitor
Morris, in Kidney Transplantation–Principles and Practice (Seventh Edition), 2014
An anti-inflammatory approach to induce remission followed by maintenance therapy with immunosupressants is still the mainstay of therapy
6-Mercaptopurine (6-MP) is indicated for remission induction and maintenance therapy of acute lymphoblastic leukemia (ALL)