Purinethol: Full Drug Profile

Purinethol - General Information

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. [PubChem]

Pharmacology of Purinethol

Purinethol is one of a large series of purine analogues which interfere with nucleic acid biosynthesis and has been found active against human leukemias. It is an analogue of the purine bases adenine and hypoxanthine. 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.

Purinethol for patients

Patients should be informed that the major toxicities of PURINETHOL are related to myelosuppression, hepatotoxicity, and gastrointestinal toxicity. Patients should never be allowed to take the drug without medical supervision and should be advised to consult their physician if they experience fever, sore throat, jaundice, nausea, vomiting, signs of local infection, bleeding from any site, or symptoms suggestive of anemia. Women of childbearing potential should be advised to avoid becoming pregnant.

Purinethol Interactions

When allopurinol and mercaptopurine are administered concomitantly, it is imperative that the dose of mercaptopurine be reduced to one third to one quarter of the usual dose. Failure to observe this dosage reduction will result in a delayed catabolism of mercaptopurine and the strong likelihood of inducing severe toxicity.

There is usually complete cross-resistance between mercaptopurine and thioguanine.

The dosage of mercaptopurine may need to be reduced when this agent is combined with other drugs whose primary or secondary toxicity is myelosuppression. Enhanced marrow suppression has been noted in some patients also receiving trimethoprim-sulfamethoxazole.

Inhibition of the anticoagulant effect of warfarin, when given with mercaptopurine, has been reported.

As there is in vitro evidence that aminosalicylate derivatives (e.g., olsalazine, mesalazine, or sulphasalazine) inhibit the TPMT enzyme, they should be administered with caution to patients receiving concurrent mercaptopurine therapy.

Purinethol Contraindications

PURINETHOL should not be used unless a diagnosis of acute lymphatic leukemia has been adequately established and the responsible physician is knowledgeable in assessing response to chemotherapy.

PURINETHOL should not be used in patients whose disease has demonstrated prior resistance to this drug. In animals and humans, there is usually complete cross-resistance between mercaptopurine and thioguanine.

PURINETHOL should not be used in patients who have a hypersensitivity to mercaptopurine or any component of the formulation.

Additional information about Purinethol

Purinethol Indication

For remission induction and maintenance therapy of acute lymphatic leukemia.

Mechanism Of Action

Purinethol 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).

Drug Interactions

Allopurinol Allopurinol increases the effect of thiopurine

Generic Name

Mercaptopurine

Synonyms

Mercaptopurine Monohydrate; Mercapurin; 6 MP; MP; 6-Mercaptopurine

Drug Category

Antineoplastic Agents; Antimetabolites; Purine analogues; Immunosuppressive Agents; Nucleic Acid Synthesis Inhibitors

Drug Type

Small Molecule; Approved

Other Brand Names containing Mercaptopurine

Ismipur; Leukerin; Leupurin; Mercaleukim; Mercaleukin; Mern; Puri-Nethol; Purimethol; Purinethol;

Absorption

Clinical studies have shown that the absorption of an oral dose of mercaptopurine in humans is incomplete and variable, averaging approximately 50% of the administered dose. The factors influencing absorption are unknown.

Toxicity (Overdose)

Signs and symptoms of overdosage may be immediate such as anorexia, nausea, vomiting, and diarrhea; or delayed such as myelosuppression, liver dysfunction, and gastroenteritis. The oral LD₅₀ of mercaptopurine was determined to be 480 mg/kg in the mouse and 425 mg/kg in the rat.

Protein Binding

Plasma protein binding averages 19% over the concentration range 10 to 50 µg/mL (a concentration only achieved by intravenous administration of mercaptopurine at doses exceeding 5 to 10 mg/kg).

Biotransformation

Hepatic. Degradation primarily by xanthine oxidase. The catabolism of mercaptopurine and its metabolites is complex. In humans, after oral administration of ³⁵S-6-mercaptopurine, urine contains intact mercaptopurine, thiouric acid (formed by direct oxidation by xanthine oxidase, probably via 6-mercapto-8-hydroxypurine), and a number of 6-methylated thiopurines. The methylthiopurines yield appreciable amounts of inorganic sulfate.

Half Life

Triphasic: 45 minutes, 2.5 hours, and 10 hours.

Dosage Forms of Purinethol

Tablet Oral

Chemical IUPAC Name

3,7-dihydropurine-6-thione

Chemical Formula

C5H4N4S

Mercaptopurine on Wikipedia

https://en.wikipedia.org/wiki/Mercaptopurine

Organisms Affected

Humans and other mammals