Mercaptopurine

Usage

Mercaptopurine is primarily used to treat acute lymphoblastic leukemia (ALL) as part of a combination chemotherapy maintenance regimen. It is also sometimes used for other types of leukemia (acute myeloid leukemia, chronic myeloid leukemia), Crohn’s disease, and ulcerative colitis. It is classified as an antimetabolite, specifically a purine analog. Mercaptopurine works by interfering with DNA and RNA synthesis, thereby inhibiting cell growth, particularly rapidly dividing cells like cancer cells and immune cells.

Alternate Names

Mercaptopurine is also known as 6-mercaptopurine (6-MP). A common brand name is Purinethol.

How It Works

Pharmacodynamics: Mercaptopurine is a prodrug that is converted to active metabolites, primarily thioguanine nucleotides (TGNs). These metabolites interfere with nucleic acid synthesis, disrupt DNA and RNA production, and ultimately inhibit cell proliferation. Its immunosuppressive effects are likely mediated through the incorporation of thioguanine into DNA, triggering apoptosis in lymphocytes.

Pharmacokinetics:

• Absorption: Oral absorption is incomplete and highly variable (5-35%), influenced by first-pass metabolism in the liver. Food can reduce bioavailability. Milk inhibits absorption due to xanthine oxidase activity.
• Metabolism: Extensive hepatic metabolism via several pathways, including hypoxanthine-guanine phosphoribosyl transferase (HGPRT) and thiopurine methyltransferase (TPMT). Genetic variations in TPMT can significantly affect metabolism and toxicity.
• Elimination: Primarily through hepatic metabolism with renal excretion of inactive metabolites; a small percentage of the drug is excreted unchanged in urine and feces.

Mode of Action: Mercaptopurine competes with purine bases (hypoxanthine and guanine) for HGPRT, leading to the formation of thioinosinic acid (TIMP). TIMP is then further metabolized to other thioguanine nucleotides (TGNs), which are the main active metabolites. These TGNs get incorporated into DNA and RNA, disrupting cell division and causing cell death. TPMT activity plays a crucial role, as low TPMT can lead to an accumulation of TGNs and increase the risk of toxicity.

Dosage

Standard Dosage

Adults:

• ALL Induction: 2.5 mg/kg orally once daily (usually 100-200 mg/day). Dose may be increased after 4 weeks if needed.
• ALL Maintenance: 1.5-2.5 mg/kg orally once daily.
• Inflammatory Bowel Disease: 1-1.5 mg/kg orally once daily, usually in the evening. Maximum dose: 75 mg/day.

Children:

• ALL Induction: 1.25-2.5 mg/kg (50-75 mg/m²) orally once daily.
• ALL Maintenance: 1.5-2.5 mg/kg orally once daily in combination with methotrexate.

Special Cases:

• Elderly Patients: Monitor renal and hepatic function. Dosage adjustments may be necessary.
• Patients with Renal Impairment: Reduce starting dose and monitor closely.
• Patients with Hepatic Dysfunction: Reduce starting dose and monitor closely.
• Patients with Comorbid Conditions: Exercise caution in patients with pre-existing infections, liver disease, or a history of cancer. TPMT activity should be tested before starting therapy.

Clinical Use Cases

Mercaptopurine is not typically used for intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations like status epilepticus or cardiac arrest.

Dosage Adjustments

Reduce the dose to 25-33% of the usual dose when co-administered with allopurinol. Doses should be individualized based on TPMT and NUDT15 activity. Patients with TPMT deficiency may require significantly reduced doses to avoid severe myelosuppression.

Side Effects

Common Side Effects:

Nausea, vomiting, diarrhea, loss of appetite, itching, skin rash, darkening of skin.

Rare but Serious Side Effects:

Liver toxicity (jaundice, abdominal pain), bone marrow suppression (easy bruising or bleeding, unusual tiredness, pale skin, signs of infection), increased risk of secondary cancers (lymphoma, skin cancer).

Long-Term Effects:

Increased risk of secondary cancers with prolonged use.

Adverse Drug Reactions (ADR):

Severe myelosuppression, hepatotoxicity, hypersensitivity reactions (rash, fever, arthralgia).

Contraindications

Hypersensitivity to mercaptopurine or azathioprine, prior resistance to mercaptopurine or thioguanine, pregnancy (unless the benefit outweighs the risk).

Drug Interactions

Allopurinol requires a dose reduction of mercaptopurine to 25-33% of the usual dose. Other interactions include:

• Other myelosuppressive agents: Increased risk of bone marrow suppression.
• Immunosuppressants: Increased risk of infection.
• Warfarin: Altered anticoagulant effects.
• Febuxostat: Contraindicated due to increased toxicity.
• Hormonal contraceptives: Reduced effectiveness of birth control pills.

Pregnancy and Breastfeeding

Mercaptopurine is contraindicated during pregnancy unless the potential benefit outweighs the potential risk to the fetus. It is excreted in breast milk and may cause harm to the nursing infant; a decision should be made whether to discontinue breastfeeding or discontinue the drug.

Drug Profile Summary

• Mechanism of Action: Purine antimetabolite that disrupts nucleic acid synthesis and inhibits cell proliferation.
• Side Effects: Nausea, vomiting, diarrhea, myelosuppression, hepatotoxicity.
• Contraindications: Hypersensitivity, prior resistance, pregnancy (unless benefits outweigh risks).
• Drug Interactions: Allopurinol, other myelosuppressive agents, immunosuppressants, warfarin.
• Pregnancy & Breastfeeding: Contraindicated in pregnancy (unless clearly necessary) and caution advised during breastfeeding.
• Dosage: Varies depending on indication and patient-specific factors (TPMT activity, age, organ function).
• Monitoring Parameters: Complete blood counts, liver function tests, TPMT activity.

Popular Combinations

Mercaptopurine is often used in combination with other chemotherapeutic agents in ALL treatment protocols, such as methotrexate, vincristine, and prednisone.

Precautions

Test TPMT activity before initiating therapy. Closely monitor blood counts and liver function. Patients should be monitored for signs of infection, bleeding, and hepatotoxicity.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Mercaptopurine?

A: The dosage varies depending on the indication, age, and other patient-specific factors. For ALL in adults, the induction dose is 2.5 mg/kg daily, while the maintenance dose is 1.5-2.5 mg/kg daily. For children with ALL, the dosage is similar. Dose adjustments are necessary for patients with renal or hepatic impairment and those with TPMT deficiency.

Q2: How should TPMT activity be used to guide Mercaptopurine dosing?

A: Patients with low or absent TPMT activity are at increased risk of severe myelosuppression. Dosage should be significantly reduced in these patients.

Q3: What are the most common side effects of Mercaptopurine?

A: Nausea, vomiting, diarrhea, and loss of appetite are common side effects.

Q4: What are the signs of Mercaptopurine toxicity?

A: Signs of toxicity include severe myelosuppression (low blood counts, increased infections, easy bruising/bleeding), hepatotoxicity (jaundice, abdominal pain), and gastrointestinal problems (severe nausea, vomiting, diarrhea).

Q5: Can Mercaptopurine be used during pregnancy?

A: Mercaptopurine should generally be avoided during pregnancy, especially in the first trimester, due to the risk of fetal harm. If absolutely necessary, it should be used with extreme caution and under close monitoring.

Q6: Is it safe to breastfeed while taking Mercaptopurine?

A: Mercaptopurine is present in breast milk and may pose a risk to the nursing infant. The decision to breastfeed or discontinue the drug should be made in consultation with a physician, considering the risks and benefits for both the mother and the infant.

Q7: What should patients be advised before starting Mercaptopurine?

A: Patients should be informed about the potential benefits and risks of the drug, including the possibility of serious side effects. They should also be advised to report any signs of infection, bleeding, or liver problems to their doctor immediately.

Q8: How does Allopurinol interact with Mercaptopurine?

A: Allopurinol inhibits the enzyme xanthine oxidase, which is involved in the metabolism of Mercaptopurine. When these drugs are used together, the dose of Mercaptopurine should be reduced to 25-33% of the usual dose to avoid toxicity.

Q9: Is there a risk of secondary cancers with Mercaptopurine?

A: Long-term use of Mercaptopurine, especially in combination with other chemotherapy drugs, may increase the risk of developing certain types of cancer, such as lymphoma and skin cancer.

Q10: What are the key monitoring parameters for patients taking Mercaptopurine?

A: Regular monitoring of complete blood counts (CBC) and liver function tests (LFTs) is essential during Mercaptopurine therapy to detect and manage potential toxicity. TPMT and NUDT15 activity should also be assessed before initiating treatment.