indication

For remission induction and maintenance therapy of acute lymphatic leukemia.

pharmacology

Mercaptopurine 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.

mechanism of action

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).

toxicity

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.

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.

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.

half life

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

drug interactions

Acenocoumarol: Mercaptopurine may decrease the anticoagulant effect of acenocoumarol.

Allopurinol: Allopurinol may increase the effect of thiopurine, mercaptopurine.

Aminosalicylic Acid: Aminosalicylic acid may increase the toxicity of thiopurine, mercaptopurine.

Anisindione: Mercaptopurine may decrease the anticoagulant effect of anisindione.

Atracurium: The agent dereases the effect of the muscle relaxant

Dicumarol: Mercaptopurine may decrease the anticoagulant effect of dicumarol.

Doxacurium chloride: The agent dereases the effect of the muscle relaxant

Mesalazine: Mesalazine may increase the toxicity of thiopurine, mercaptopurine.

Metocurine: The agent dereases the effect of the muscle relaxant

Mivacurium: The agent dereases the effect of the muscle relaxant

Olsalazine: Olsalazine may increase the toxicity of thiopurine, mercaptopurine.

Pancuronium: The agent dereases the effect of the muscle relaxant

Sulfasalazine: Sulfasalazine may increase the toxicity of thiopurine, mercaptopurine.

Thioguanine: Complete cross resistance may occur.

Trastuzumab: Trastuzumab may increase the risk of neutropenia and anemia. Monitor closely for signs and symptoms of adverse events.

Tubocurarine: The agent dereases the effect of the muscle relaxant

Vecuronium: The agent dereases the effect of the muscle relaxant

Warfarin: Mercaptopurine may decrease the anticoagulant effect of warfarin.