Mercaptopurine; Uses, Dosage, Side Effects, Drug Interactions

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Mercaptopurine is an antimetabolite antineoplastic agent with immunosuppressant properties. It interferes with nucleic acid synthesis by inhibiting purine metabolism and is used, usually in combination with other drugs, in the treatment of or in remission maintenance programs for leukemia.

Mercaptopurine Anhydrous is the anhydrous form of mercaptopurine, a thiopurine-derivative antimetabolite with antineoplastic and immunosuppressive activities. Produced through the metabolism of mercaptopurine by hypoxanthine-guanine phosphoribosyltransferase (HGPRT), mercaptopurine metabolites 6-thioguanosine-5′-phosphate (6-thioGMP) and 6-thioinosine monophosphate (T-IMP) inhibit nucleotide interconversions and de novo purine synthesis, thereby blocking the formation of purine nucleotides and inhibiting DNA synthesis. This agent is also incorporated into DNA in the form of deoxythioguanosine, which results in the disruption of DNA replication. In addition, mercaptopurine is converted to 6-methylmercaptopurine ribonucleoside (MMPR) by 6-thiopurine methyltransferase; MMPRs are also potent inhibitors of de novo purine synthesis.

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Mercaptopurine is a medication used for cancer and autoimmune diseases. Specifically, it is used to treat acute lymphocytic leukemia (ALL), chronic myeloid leukemia (CML), Crohn’s disease, and ulcerative colitis. For ALL it is generally used with methotrexate. It is taken by mouth. It is an antimetabolite antineoplastic agent with immunosuppressant properties. It interferes with nucleic acid synthesis by inhibiting purine metabolism and is used, usually in combination with other drugs, in the treatment of or in remission maintenance programs for leukemia.

Mechanism of action of Mercaptopurine

Mercaptopurine competes with hypoxanthine and guanine for the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRTase) and is itself converted to thioinosinic acid (TIMP). This intracellular nucleotide inhibits several reactions involving inosinic acid (IMP), including the conversion of IMP to xanthylic acid (XMP) and the conversion of IMP to adenylic acid (AMP) via adenylosuccinate (SAMP). In addition, 6-methylthioinosinate (MTIMP) is formed by the methylation of TIMP. Both TIMP and MTIMP have been reported to inhibit glutamine-5-phosphoribosylpyrophosphate amidotransferase, the first enzyme unique to the de novo pathway for purine ribonucleotide synthesis. Experiments indicate that radiolabeled mercaptopurine may be recovered from the DNA in the form of deoxythioguanosine. Some mercaptopurine is converted to nucleotide derivatives of 6-thioguanine (6-TG) by the sequential actions of inosinate (IMP) dehydrogenase and xanthylate (XMP) aminase, converting TIMP to thioguanylic acid (TGMP).

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Indications of Mercaptopurine

  • Crohn’s disease, 
  • Acute lymphoblastic leukemia
  • Autoimmune hepatitis
  • Inflammatory bowel disease
  • Intestinal arterial insufficiency
  • Ulcerative colitis, maintenance
  • Acute lymphoblastic leukemias
  • Acute promyelocytic leukemia
  • Hepatitis, autoimmune
  • Lymphoma, lymphoblastic
  • Ulcerative colitis
  • Mercaptopurine is approved to be used with other drugs to treat: Acute lymphoblastic leukemia (ALL). It is used as maintenance therapy in adults and children.
  • Mercaptopurine tablets are indicated for maintenance therapy of acute lymphatic (lymphocytic, lymophoblastic) leukemia as part of a combination regimen. The response to this agent depends upon the particular subclassification of acute lymphatic leukemia and the age of the patient (pediatric or adult).
  • Mercaptopurine is not effective prophylaxis or treatment of central nervous system leukemia.
  • Mercaptopurine is also being studied in the treatment of other types of cancer.

Contra-Indications of Mercaptopurine

  • Extreme loss of body water
  • Decreased function of bone marrow
  • Anemia
  • Decreased blood platelets
  • Decreased white blood cells
  • Decreased neutrophils a type of white blood cell
  • Stomach or intestinal ulcer
  • Liver Problems
  • Blockage of normal bile flow
  • Acute inflammation of the pancreas
  • kidney disease with a reduction in kidney function
  • The high amount of bilirubin in the blood
  • Ascites
  • Abnormal liver function tests
  • Pregnancy
  • Thiopurine S-methyltransferase deficiency
  • Hepatosplenic T-cell lymphoma

Dosage of Mercaptopurine

Strengths: 50 mg; 100 mg/5 mL

Acute Lymphoblastic Leukemia

Initial Dosage

  • Oral: 2.5 mg/kg of body weight per day (100 to 200 mg in the average adult). This dose may be continued daily for several weeks or more in some patients. If, after 4 weeks at this dosage, there is no clinical improvement and no definite evidence of leukocyte or platelet depression, the dosage may be increased up to 5 mg/kg daily. A dosage of 2.5 mg/kg per day may result in a rapid fall in leukocyte count within 1 to 2 weeks in some adults with acute lymphatic leukemia and high total leukocyte counts.
  • The total daily dosage may be given at one time. It is calculated to the nearest multiple of 25 mg.

Crohn’s Disease – Acute stage

  • Oral: 1.0 to 1.5 mg/kg of body weight per day

Crohn’s Disease – Maintenance

  • Oral: 1.0 to 1.5 mg/kg of body weight per day
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Ulcerative Colitis – Maintenance

  • Oral: 1.0 to 1.5 mg/kg of body weight per day

Inflammatory Bowel Disease

  • Oral: 1.0 to 1.5 mg/kg of body weight per day

Pediatric Intestinal Arterial Insufficiency

Initial Dosage

  • Oral: 2.5 mg/kg of body weight per day (50 mg in an average 5-year-old child). Pediatric patients with acute leukemia have tolerated this dose without difficulty in most cases; it may be continued daily for several weeks or more in some patients. If, after 4 weeks at this dosage, there is no clinical improvement and no definite evidence of leukocyte or platelet depression, the dosage may be increased up to 5 mg/kg daily. A dosage of 2.5 mg/kg per day may result in a rapid fall in leukocyte count within 1 to 2 weeks in some adults with acute lymphatic leukemia and high total leukocyte counts.
  • The total daily dosage may be given at one time. It is calculated to the nearest multiple of 25 mg.

Side effects of Mercaptopurine

The most common

More common

Less common

Drug Interactions of Mercaptopurine

Mercaptopurine may interact with following drugs, suppliments & may change the drug efficasy

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Pregnancy & Lactation of Mercaptopurine

FDA Pregnancy Category D

Pregnancy

There is a possibility of a birth defect if either the man or woman is using mercaptopurine at the time of conception, or if it is taken during pregnancy. Effective birth control should be practiced while using this medication. This medication should not be used during pregnancy unless the benefits outweigh the risks. If you become pregnant while you or your partner are taking this medication, contact your doctor immediately.

Lactation

This medication passes into breast milk. Because of the risks associated with mercaptopurine, a decision should be made to cease breastfeeding or discontinue the medication, taking into account the importance of the medication to the mother. Women who are taking this medication should not breastfeed.

References

 

Mercaptopurine

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