6-Methylmercaptopurine

6-Methylmercaptopurine (6-MMP) is a significant metabolite derived from the metabolism of thiopurine drugs like azathioprine and mercaptopurine, which are extensively used to treat autoimmune diseases and certain cancers. 

The metabolism of these drugs involves several pathways, with 6-MMP being a key product formed through the methylation of mercaptopurine by the enzyme thiopurine S-methyltransferase (TPMT). 

Monitoring 6-MMP levels is crucial for optimizing therapy and avoiding toxicity. 

Normal levels of 6-MMP are typically below 5700 pmol/8x10^8 RBCs, as higher levels are linked to an increased risk of hepatotoxicity. 

Assessing 6-MMP alongside thioguanine nucleotide (TGN) levels helps in personalizing treatment plans, ensuring therapeutic efficacy, and identifying issues such as noncompliance, metabolic diversion, or excessive metabolite production.

What is 6-Methylmercaptopurine (6-MMP)?

6-Methylmercaptopurine (6-MMP) is a metabolite of thiopurine drugs, such as azathioprine and mercaptopurine (also known as 6-MP), which are commonly used in the treatment of autoimmune diseases and certain types of cancer. The metabolism of thiopurine drugs involves several pathways, with 6-MMP being one of the key metabolites. [4.] 

Thiopurine Drugs Overview [2., 5.]

Thiopurine drugs like azathioprine and mercaptopurine are immunosuppressive agents widely used in the treatment of various autoimmune and inflammatory conditions, as well as certain cancers. Understanding their metabolism is crucial for optimizing therapy and monitoring for potential toxicities.

Mercaptopurine (6-MP)

Drug Class

Mercaptopurine is considered a gastrointestinal agent, an antineoplastic agent, a cytotoxic antirheumatic agent, an antimetabolite and a musculoskeletal agent. 

‍Mechanism of Action

Mercaptopurine is a purine analog that, once inside cells, is activated to form metabolites including thioguanine nucleotides (TGNs). These TGNs incorporate into DNA or RNA, leading to cell-cycle arrest and cell death. 

Additionally, mercaptopurine metabolites inhibit purine synthesis and purine nucleotide interconversions, further disrupting cellular functions and contributing to its therapeutic effects.

Azathioprine

Drug Class

Azathioprine is considered a gastrointestinal agent, a cytotoxic antirheumatic, an antimetabolite and a musculoskeletal agent.

Mechanism of Action

Azathioprine, an imidazolyl derivative of and precursor to 6-mercaptopurine, functions as an immunosuppressive antimetabolite. 

While the precise mechanism of its immunosuppressive action is not fully understood due to the complexity of the immune response, azathioprine is known to suppress cell-mediated hypersensitivities and alter antibody production.

Conditions Commonly Treated with Thiopurine Drugs

Conditions Commonly Treated with Mercaptopurine

• Acute Lymphoid Leukemia

• Chronic Myeloid Leukemia

• Crohn's Disease

• Ulcerative Colitis

• Non-Hodgkin's Lymphoma

Conditions Commonly Treated by Azathioprine

• Atopic Dermatitis

• Autoimmune Hepatitis 

• Behcet's Syndrome

• Cardiac Transplant Rejection Prophylaxis

• Crohn's Disease

• Eosinophilic Granulomatosis with Polyangiitis

• Granulomatosis with Polyangiitis

• Lung Transplant Rejection Prophylaxis

• Lupus Nephritis (maintenance following adequate response to induction therapy)

• Microscopic Polyangiitis

• Myasthenia Gravis

• Pemphigus

• Polyarteritis Nodosa

• Renal Transplant Rejection Prophylaxis

• Rheumatoid Arthritis

• Systemic Lupus Erythematosus

• Thyroid Eye Disease, moderate to severe

• Ulcerative Colitis

• Warm Autoimmune Hemolytic Anemia

Thiopurine Metabolism Overview [5.] 

Conversion Process

Azathioprine (AZA) is a prodrug converted to mercaptopurine (6-MP) via biogenic thiols.

6-MP then undergoes three competing metabolic pathways.

Metabolic Pathways of 6-MP

1. Degradation to thiouric acid (TUA), which is excreted.

2. Methylation by thiopurine S-methyltransferase (TPMT) to form 6-methylmercaptopurine (6-MMP).

3. Conversion to thioinosine monophosphate (TIMP) via hypoxanthine phosphoribosyltransferase (HPRT). TIMP is further metabolized to thioguanine nucleotides (TGNs).

TGNs are the active immunosuppressive metabolites of these drugs, and testing for TGN levels alongside 6-MMP levels can help determine if a patient is within a therapeutic window, is using an alternative (hypermethylation) pathway to break down the drugs, or if the patient is noncompliant with their medication plan. [1., 5.] 

Hyper-methylation, where there is an excessive production of 6-MMP relative to TGNs, can lead to poor therapeutic response and hepatotoxicity.  [5.] 

Strategies to manage side effects include dose splitting or combining low-dose thiopurine with allopurinol, which helps optimize the balance between TGNs and 6-MMP. [5.]

Clinical Significance of 6-MMP

Regular measurement of TGNs and 6-MMP levels in red blood cells is recommended to determine an individual’s therapeutic window, which is typically reached 3-6 months after initiation of therapy. [1.] 

Monitoring TGN levels can guide dosing to improve clinical outcomes. In cases of subtherapeutic TGNs, dose adjustments are made to reach therapeutic levels. [5.] 

TGNs should be measured 4 weeks after starting thiopurines or following any dose changes. Routine checks help ensure effective therapy and manage any potential side effects early. [5.] 

Therapeutic ranges for TGNs are between 235-450 pmol/8×10^8 RBCs. High 6-MMP levels (>5700 pmol/8×10^8 RBCs) are associated with hepatotoxicity. [5.] 

For unresponsive patients, consider the following: [1.] 

• Noncompliance: low 6-MMP and low 6-TG levels indicate patients not taking their medications.

• Metabolite Diversion: low 6-TG and normal or increased 6-MMP suggest diversion of metabolites away from 6-TG production.

• Refractory to Treatment: adequate 6-TG levels but lack of clinical response indicates treatment resistance.

• Hepatotoxicity Risk: increased 6-MMP or a high 6-MMP:6-TG ratio with adequate 6-TG levels may lead to increased hepatotoxicity.

Laboratory Testing for 6-MMP

Test Information, Sample Collection and Preparation 

6-MMP levels can be measured in various biological samples including whole blood and red blood cells (RBCs). Whole blood and RBC samples are commonly used, as 6-MMP is primarily present in erythrocytes due to its high affinity for red blood cell proteins.

Sample collection requires a venipuncture procedure. Speak to the ordering provider prior to sample collection, as a trough specimen (sample collection within one hour of next recommended dose) may be required. [3.] 

Interpretation of 6-MMP Test Results

Optimal Levels of 6-MMP Levels

Test results must be interpreted within the context of an individual’s clinical context and alongside levels of 6-TG.  

Optimal RBC levels are given by one laboratory as: [3.] 

6-TG 235-400 pmol/8x10(8) RBC

6-MMP <5700 pmol/8x10(8) RBC

Another resource states that the recommended therapeutic range for 6-TG is 235-450 pmol/8×10^8 RBCs. [5.] 

Clinical Significance of Increased 6-MMP Levels

Increased 6-MMP levels are commonly associated with hepatotoxicity, although it may also indicate metabolic diversion. [1., 5.] 

Clinical Significance of Decreased 6-MMP Levels

Decreased 6-MMP levels are associated with noncompliance or altered thiopurine metabolism. [1., 5.] 

FAQ: Understanding 6-MMP

6-MMP (6-methylmercaptopurine) is a metabolite of the immunosuppressive drug 6-mercaptopurine (6-MP), commonly used in the treatment of certain types of leukemia and autoimmune diseases. 

Monitoring 6-MMP levels is crucial for optimizing therapy and minimizing adverse effects. This FAQ section addresses common questions about 6-MMP, its significance, and related health concerns.

What is 6-MMP?

6-MMP (6-methylmercaptopurine) is a metabolite produced during the metabolism of 6-mercaptopurine (6-MP). 6-MP is an immunosuppressive drug used to treat acute lymphoblastic leukemia (ALL), inflammatory bowel disease (IBD), and other autoimmune conditions. 

6-MMP levels are measured to monitor and adjust treatment efficacy and safety.

Why is it Important to Monitor 6-MMP Levels?

Monitoring 6-MMP levels is important because it helps ensure the effectiveness of 6-MP therapy while minimizing the risk of adverse effects, such as hepatotoxicity. 

By measuring 6-MMP levels, healthcare providers can adjust dosages to maintain therapeutic effectiveness and reduce the risk of toxicity.

What is Considered a Normal 6-MMP Level?

A normal 6-MMP level is typically reported as being below 5700 pmol/8x10^8 RBCs, as levels above this range are associated with hepatotoxicity, or liver damage. [5.] 

What is 6-MMP Hepatotoxicity?

6-MMP hepatotoxicity refers to liver damage caused by elevated levels of 6-MMP. Symptoms of hepatotoxicity may include jaundice (yellowing of the skin and eyes), elevated liver enzymes, fatigue, nausea, and abdominal pain. Monitoring and managing 6-MMP levels is crucial to prevent and address hepatotoxicity.

How Can Elevated 6-MMP Levels Be Managed?

Elevated 6-MMP levels can be managed by adjusting the dosage of 6-MP or switching to alternative therapies if necessary. Healthcare providers may also recommend regular monitoring of liver function tests and other blood parameters to ensure patient safety and effective treatment.

Are There Any Ways to Prevent 6-MMP Hepatotoxicity?

Preventing 6-MMP hepatotoxicity involves regular monitoring of 6-MMP levels and liver function tests, adhering to prescribed dosages, and promptly reporting any symptoms of liver dysfunction to healthcare providers. Personalized dosing strategies based on metabolite monitoring can help minimize the risk of hepatotoxicity.

When Should I Consult a Healthcare Provider about 6-MMP Levels?

Consult a healthcare provider if you are undergoing treatment with 6-MP and experience symptoms such as jaundice, fatigue, nausea, or abdominal pain. Regular follow-ups and monitoring of 6-MMP levels and liver function tests are essential for managing therapy effectively and safely.

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