PURI-NETHOL

Indications

• Acute leukaemias
• Chronic myeloid leukaemia
• Severe acute Crohn’s disease
• Maintenance of remission of Crohn’s disease

Mechanism of action

Mercaptopurine competes with hypoxanthine and guanine for the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRTase) and is converted to thioinosinic acid (TIMP). TIMP inhibits several reactions involving inosinic acid (IMP), including the conversion of IMP to xanthylic acid (XMP) and adenylic acid (AMP). TIMP can further be methylated to produce 6-methylthioinosinate (MTIMP), which inhibits glutamine-5-phosphoribosylpyrophosphate amidotransferase, a key enzyme in the de novo purine synthesis pathway. Additionally, mercaptopurine metabolites may integrate into DNA, affecting normal cellular processes.

Pharmacodynamics

Mercaptopurine is an analogue of purine bases adenine and hypoxanthine, which interferes with nucleic acid biosynthesis. Its active metabolites exert cytotoxic effects primarily against rapidly dividing cells, making it effective in treating leukemias. The precise mechanisms through which mercaptopurine induces cell death remain complex and not fully understood, involving multiple biochemical pathways.

Pharmacokinetics

Mercaptopurine is well absorbed from the gastrointestinal tract, with its bioavailability affected by factors such as food intake and concurrent medications. It undergoes extensive hepatic metabolism, primarily involving thiopurine methyltransferase (TPMT), which is crucial for its detoxification. The drug is eliminated via renal pathways, and dose adjustments may be necessary in patients with renal impairment. Monitoring of liver function and hematological parameters is essential during treatment due to the risk of myelosuppression.

Contra-indications

• Absent thiopurine methyltransferase activity
• Severe ulcerative colitis

Adverse effects

• Anaemia
• Appetite decreased
• Bone marrow depression
• Diarrhoea
• Hepatic disorders
• Hepatotoxicity (more common at high doses)
• Leucopenia
• Nausea
• Oral disorders
• Pancreatitis
• Thrombocytopenia
• Vomiting
• Fever
• Increased risk of infection
• Neutropenia
• Rash
• Agitation
• Arrhythmia
• Coma
• Heart failure
• Seizure
• Severe cutaneous adverse reactions (SCARs)

Interactions

• Febuxostat increases exposure to mercaptopurine (severe interaction)
• Allopurinol increases risk of haematological toxicity (unknown interaction)
• Coumarins may decrease anticoagulant effect (unknown interaction)
• Live vaccines increase risk of generalised infection (possibly life-threatening) (unknown interaction)
• Trimethoprim increases risk of haematological toxicity in renal transplant patients (unknown interaction)

Precautions

• Use with caution in renal impairment
• Consider measuring thiopurine methyltransferase (TPMT) activity before starting therapy
• Monitor liver function during treatment

Pregnancy

Mercaptopurine is classified as a Category D drug; there is evidence of human fetal risk, but benefits may warrant use despite risks.

Breast-feeding

It is not known whether mercaptopurine is excreted in human milk. Caution is advised when administering to nursing mothers.

Storage

Store at room temperature, away from moisture and heat. Keep out of reach of children.

Formulations

• Mercaptopurine 10 mg tablets
• Mercaptopurine 50 mg tablets
• Xaluprine 20 mg/ml oral suspension

Mechanism of action

Mercaptopurine competes with hypoxanthine and guanine for the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRTase) and is itself converted to thioinosinic acid (TIMP). TIMP inhibits several reactions that involve inosinic acid (IMP), such as the conversion of IMP to xanthylic acid (XMP) and the conversion of IMP to adenylic acid (AMP) via adenylosuccinate (SAMP). Upon methylation, TIMP forms 6-methylthioinosinate (MTIMP) which inhibits glutamine-5-phosphoribosylpyrophosphate amidotransferase in addition to TIMP. Glutamine-5-phosphoribosylpyrophosphate amidotransferase is the first enzyme unique to the _de novo_ pathway for purine ribonucleotide synthesis. According to experimental findings using radiolabeled mercaptopurine, mercaptopurine may be recovered from the DNA in the form of deoxythioguanosine. In comparison, some mercaptopurine may be converted to nucleotide derivatives of 6-thioguanine (6-TG) via actions of inosinate (IMP) dehydrogenase and xanthylate (XMP) aminase that convert TIMP to thioguanylic acid (TGMP). The pathogenesis of several neurodegenerative diseases often involves the microglial activation and associated inflammatory processes. Activated microglia release pro-inflammatory factors that may be neurotoxic. 6-Mercaptopurine (6-MP) is a well-established immunosuppressive drug. Common understanding of their immunosuppressive properties is largely limited to peripheral immune cells. However, the effect of 6-MP in the central nervous system, especially in microglia in the context of neuroinflammation is, as yet, unclear. Tumor necrosis factor-alpha (TNF-a) is a key cytokine of the immune system that initiates and promotes neuroinflammation. The present study aimed to investigate the effect of 6-MP on TNF-a production by microglia to discern the molecular mechanisms of this modulation. Lipopolysaccharide (LPS) was used to induce an inflammatory response in cultured primary microglia or murine BV-2 microglial cells. Released TNF-a was measured by enzyme-linked immunosorbent assay (ELISA). Gene expression was determined by real-time reverse transcription polymerase chain reaction (RT-PCR). Signaling molecules were analyzed by western blotting, and activation of NF-kB was measured by ELISA-based DNA binding analysis and luciferase reporter assay. Chromatin immunoprecipitation (ChIP) analysis was performed to examine NF-kB p65 and coactivator p300 enrichments and histone modifications at the endogenous TNF-a promoter. Treatment of LPS-activated microglia with 6-MP significantly attenuated TNF-a production. In 6-MP pretreated microglia, LPS-induced MAPK signaling, I?B-a degradation, NF-kB p65 nuclear translocation, and in vitro p65 DNA binding activity were not impaired. However, 6-MP suppressed transactivation activity of NF-?B and TNF-a promoter by inhibiting phosphorylation and acetylation of p65 on Ser276 and Lys310, respectively. ChIP analyses revealed that 6-MP dampened LPS-induced histone H3 acetylation of chromatin surrounding the TNF-a promoter, ultimately leading to a decrease in p65/coactivator-mediated transcription of TNF-a gene. Furthermore, 6-MP enhanced orphan nuclear receptor Nur77 expression. Using RNA interference approach, we further demonstrated that Nur77 upregulation contribute to 6-MP-mediated inhibitory effect on TNF-a production. Additionally, 6-MP also impeded TNF-a mRNA translation through prevention of LPS-activated PI3K/Akt/mTOR signaling cascades. These results suggest that 6-MP might have a therapeutic potential in neuroinflammation-related neurodegenerative disorders through downregulation of microglia-mediated inflammatory processes. Mercaptopurine (6-MP) competes with hypoxanthine and guanine for the enzyme hyphoxanthine-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 co

Pharmacodynamics

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.