Mercaptopurine

Mercaptopurine

Systematic (IUPAC) name
3,7-dihydropurine-6-thione
Clinical data
Trade names	Purinethol
AHFS/Drugs.com	monograph
MedlinePlus	a682653
Pregnancy category	D
Legal status	℞ (Prescription only)
Routes of administration	Oral
Pharmacokinetic data
Bioavailability	5 to 37%
Metabolism	xanthine oxidase
Biological half-life	60 to 120 min., longer for its active metabolites
Excretion	Kidney
Identifiers
CAS Number	50-44-2 Y
ATC code	L01BB02 (WHO)
PubChem	CID: 667490
IUPHAR/BPS	7226
DrugBank	DB01033 Y
ChemSpider	580869 Y
UNII	PKK6MUZ20G Y
KEGG	D04931 Y
ChEBI	CHEBI:50667 Y
ChEMBL	CHEMBL1425 Y
Chemical data
Formula	C5H4N4S
Molecular mass	152.177 g/mol
SMILES S=C2/N=C\Nc1ncnc12
InChI InChI=1S/C5H4N4S/c10-5-3-4(7-1-6-3)8-2-9-5/h1-2H,(H2,6,7,8,9,10) Y Key:GLVAUDGFNGKCSF-UHFFFAOYSA-N Y
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Mercaptopurine (also called 6-mercaptopurine, 6-MP or its brand name Purinethol) is an immunosuppressive medication. It is used to treat acute lymphocytic leukemia, Crohn's disease, and ulcerative colitis. It is a thiopurine.

It is on the WHO Model List of Essential Medicines, the most important medications needed in a basic health system.

Medical uses

It is used to treat acute lymphocytic leukemia, Crohn's disease, and ulcerative colitis.

Side effects

Some of the adverse reactions of taking mercaptopurine will include diarrhea, nausea, vomiting, loss of appetite, fatigue, stomach/abdominal pain, weakness, skin rash, darkening of the skin, and hair loss. Serious adverse reactions include mouth sores, fever, sore throat, easy bruising or bleeding, pinpoint red spots on the skin, yellowing of eyes or skin, dark urine, and painful or difficult urination. Other more serious side effects include black or tarry stools (melena), bloody stools, and bloody urine.

Symptoms of allergic reaction to mercaptopurine include rash, itching, swelling, dizziness, trouble breathing, and inflammation of the pancreas.

Mercaptopurine causes myelosuppression, suppressing the production of white blood cells and red blood cells. It may be toxic to bone marrow. Weekly blood counts are recommended for patients on mercaptopurine. The patient should stop taking the medication at least temporarily if there is an unexplained, abnormally large drop in white blood cell count, or any other blood count.

Toxicity of mercaptopurine can be linked to genetic polymorphisms in thiopurine S-methyltransferase (TPMT) and inosine triphosphate pyrophosphatase (ITPA). Patients with specific allele variants will require dose adjustments. Caucasian patients with a variant allele of the ITPA gene, experience higher rates of febrile neuropenia than patients of other ethnic groups, due to differences in allelic frequencies among ethnicities.

Precautions

Mercaptopurine can lower the body's ability to fight off infection. Those taking it should get permission from a doctor to receive immunizations and vaccinations. It is also recommended that, while on the drug, one should avoid those having recently received oral polio vaccine.

This drug was formerly not recommended during pregnancy and early evidence indicated pregnant women on the drug (or the related azathioprine) showed a seven-fold incidence of fetal abnormalities as well as a 20-fold increase in miscarriage. There were also anecdotal reports linking mercaptopurine with spontaneous abortion, leading to the US FDA rating both AZA and mercaptopurine as category D drugs. However, Davis et al. 1999 found mercaptopurine, compared to methotrexate, was ineffective as a single-agent abortifacient; every woman in the mercaptopurine arm of the study had fetal cardiac activity at follow-up (two weeks later) and was given a suction abortion. A more recent, larger study, however, performed by the Cancers et Surrisque Associe aux Maladies inflamatoires intestinales En France (CESAME) indicated an overall rate of congenital malformations not significantly greater than the general population in France. The European Crohn's and Colitis Organisation (ECCO) concluded in a consensus paper in 2010 that while AZA and mercaptopurine have an FDA rating of D, new research in both animals and humans indicates that "thiopurines are safe and well tolerated during pregnancy."

Mercaptopurine causes changes to chromosomes in animals and humans, though a study in 1990 found, "while the carcinogenic potential of 6-MP cannot be precluded, it can be only very weak or marginal." Another study in 1999 noted an increased risk of developing leukemia when taking large doses of 6-MP with other cytotoxic drugs.

Drug interactions

Allopurinol inhibits xanthine oxidase, the enzyme that breaks down mercaptopurine. Those taking allopurinol (often used to prevent gout) are at risk for mercaptopurine toxicity. The dose should be reduced or allopurinol should be discontinued. Several published studies have demonstrated that the use of allopurinol in combination with low dose 6mp helps reduce 6mmp levels, which are toxic to liver tissue, whilst increasing the therapeutic levels of 6mp for some inflammatory conditions.

Mechanisms of action

Official information from the package insert for purinethol:

• Mercaptopurine (6-MP) competes with the purine derivatives hypoxanthine and guanine for the enzyme HGPRT and is itself converted to thio inosine monophosphate (TIMP).
  • TIMP inhibits several chemical 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).
• Animal tumors that are resistant to mercaptopurine often have lost the ability to convert mercaptopurine to TIMP. However, it is clear that resistance to mercaptopurine may be acquired by other means as well, particularly in human leukemias.
• It is not known exactly which of any one or more of the biochemical effects of mercaptopurine and its metabolites are directly or predominantly responsible for cell death.

6-MP ribonucleotide inhibits purine nucleotide synthesis and metabolism by inhibiting an enzyme called Phosphoribosyl pyrophosphate amidotransferase (PRPP Amidotransferase). PRPP Amidotransferase is the rate limiting enzyme of purine synthesis. This alters the synthesis and function of RNA and DNA. Mercaptopurine interferes with nucleotide interconversion and glycoprotein synthesis.

Pharmacogenetics

The enzyme thiopurine S-methyltransferase (TPMT) is responsible, in part, for the inactivation of 6-mercaptopurine. TPMT catalyzes the methylation of 6-mercaptopurine into the inactive metabolite 6-methylmercaptopurine - this methylation prevents mercaptopurine from further conversion into active, cytotoxic thioguanine nucleotide (TGN) metabolites. Certain genetic variations within the TPMT gene can lead to decreased or absent TPMT enzyme activity, and individuals who are homozygous or heterozygous for these types of genetic variations may have increased levels of TGN metabolites and an increased risk of severe bone marrow suppression (myelosuppression) when receiving mercaptopurine. In many ethnicities, TPMT polymorphisms that result in decreased or absent TPMT activity occur with a frequency of approximately 5%, meaning that about 0.25% of patients are homozygous for these variants. However, an assay of TPMT activity in red blood cells or a TPMT genetic test can identify patients with reduced TPMT activity, allowing for the adjustment of mercaptopurine dose or avoidance of the drug entirely. The FDA-approved drug label for mercaptopurine recommends testing for TPMT activity to identify patients at risk for myelotoxicity. Indeed, testing for TPMT activity is currently one of the few examples of pharmacogenetics being translated into routine clinical care.

See also

• Azathioprine

External links

• FDA Label, Mercaptopurine (PDF)