Mercaptopurine (Mercaptopurinum)

Pharmacodynamics Pharmacokinetics Indications Carefully Contraindications Dosing and Administration Side effects
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Clinical and pharmacological group: & nbsp

Antimetabolites

Included in the formulation
  • Mercaptopurine
    pills inwards 
    BELMEDPREPARATY, RUP     Republic of Belarus
  • Mercaptopurine-native
    pills inwards 
    NATIVA, LLC     Russia
  • Puri-Netol®
    pills inwards 
    Aspen Pharma Trading Limited    
    • Included in the list (Order of the Government of the Russian Federation No. 2782-r of 30.12.2014):

    VED

    ONLS

    АТХ:

    L.01.B.B.02   Mercaptopurine

    L.01.B.B   Purine analogues

    Pharmacodynamics:

    Purim antimetabolite. The structure is close to the purine bases (guanine, hypoxanthine, which is part of the nucleic acids). The action is phase-specific (cells in the S-phase of the cell cycle are sensitive). It is activated in tissues, competes with hypoxanthine and guanine for hypoxanthine guanine phosphoribosyltransferase, which transfers the drug to thioinosinic acid. The latter suppresses a number of reactions involving inosinic acid, including its conversion to xanthine and adenylic acids. In addition, during the methylation of thioinosinic acid, a substance is formed that blocks, along with the latter, glutamine-5-phosphoribosyl pyrophosphate aminotransferase, an enzyme that initiates the purine synthesis of ribonucleotides. Suppresses the synthesis of DNA and, to a lesser extent, RNA. Inclusion in appropriate metabolic reactions disrupts the synthesis of nucleic acids, which play an important role in the processes of tissue proliferation,including tumor ones. Resistance of tumors is often associated with the loss of the ability of cells to form thioinosinic acid.

    Pharmacokinetics:

    Absorption from the gastrointestinal tract is variable and incomplete (≤ 50%). Absolute bioavailability is lower, probably due to the effect of the first passage through the liver. It penetrates the blood-brain barrier in amounts insufficient for the treatment of neuroleukemia. Connection with plasma proteins 20% (low). Biotransformation in the liver: activation and oxidation of xanthine oxidases to active metabolites. The half-life period is three-phase: 47 minutes (in adults) and 21 minutes (in children), 2.5 hours and 10 hours. Elimination is carried out by the kidneys through tubular secretion and glomerular filtration (metabolites are detected after 2 hours after administration). 46% of the dose is excreted in the first day (7-39% unchanged). Metabolites (thiourea acid, formed as a result of direct oxidation involving xanthine oxidase, and several methylated thiopurins) and unchanged drug can be determined in urine for several weeks after discontinuation of treatment. Metabolites are pharmacologically active and have a longer half-life than actually mercaptopurine. The concentration of mercaptopurine in the plasma rarely exceeds 1-2 μg / ml, which greatly complicates the control over it during the treatment. Removed during hemodialysis.

    Indications:

    Acute lymphoblastic leukemia.

    Acute myelogenous leukemia.

    Chronic myelogenous leukemia.

    Chorionepithelioma of the uterus.

    Reticulosis.

    Chronic granulocytic leukemia.

    ICD-10

    II.C51-C58.C58   Malignant neoplasm of placenta

    II.C81-C96.C91.0   Acute lymphoblastic leukemia

    II.C81-C96.C91.1   Chronic lymphocytic leukemia

    II.C81-C96.C92.0   Acute myeloid leukemia

    II.C81-C96.C92.1   Chronic myeloid leukemia

    II.C81-C96.C96.1   Malignant histiocytosis

    Contraindications:

    Individual intolerance.

    Pregnancy and the period of breastfeeding.

    Carefully:

    Oppression of bone marrow function (leukopenia with less than 3 white blood cells×109/ l, thrombocytopenia with a platelet count of less than 100×109/ l).

    Acute viral infections.

    Fungal and bacterial diseases.

    Renal and / or hepatic insufficiency.

    Hyperuricemia.

    Gout or urate nephrourolythiasis.

    Age to 2 years.

    Patients who received previous antitumor or radiation therapy.

    Pregnancy and lactation:

    Action category for the fetus by by FDA - D. Contraindicated in pregnancy and breastfeeding.

    Dosing and Administration:

    The dosage regimen is set individually, depending on the indications and stage of the disease, the state of the hematopoiesis system, the scheme of antitumor therapy.

    Acute lymphoblastic leukemia, acute non-lymphoblastic leukemia:

    - remission induction: inside at a dose of 2.5 mg / kg (80-100 mg / m2; round to the nearest 25 mg) per day once or in several doses. In the absence of clinical improvement and a decrease in the number of white blood cells after treatment within 4 weeks, an increase in the dose to 5 mg / kg per day is possible.

    - maintenance of remission: inside at 1,5-2,5 mg / kg (50-100 mg / m2) per day.

    Chronic myeloblastic leukemia, chronic granulocytic leukemia; chorioepithelioma of the uterus, reticulosis, ulcerative colitis (resistant, often recurrent), Crohn's disease (resistant, often recurrent):

    - inside at 1,5 mg / kg per day; in the absence of clinical improvement and a decrease in the number of leukocytes, a gradual increase in the dose to 2.5 mg / kg per day is possible.

    Side effects:

    Blood: anemia, leukopenia, immunosuppression or infection, thrombocytopenia, myelosuppression, agranulocytosis, pancytopenia, bone marrow hypoplasia.

    Digestive system: loss of appetite, nausea, vomiting, stomatitis, ulcerative lesions of the gastrointestinal tract, diarrhea.

    Urinary system: an increase in the concentration of uric acid in the blood and urine, hyperuricemia or uric acid nephropathy. Possible detection in the urine of mercaptopurine crystals in children with high-dose (1 thousand mg / m2 per day) of therapy (in combination with hematuria).

    Nervous system: headache, weakness.

    Leather: skin rashes, itching, darkening of the skin.

    Allergy: drug fever.

    Reproductive system: gonadal suppression (amenorrhea or azoospermia), especially in combination with alkylating agents. Effects depend on the dose and duration of treatment and can be irreversible.

    Carcinogenicity (mutagenicity): secondary malignant tumors are a potential delayed side effect of many antitumor drugs. It is unclear whether this is due to their mutagenic or immunosuppressive effect. The effect of the dose and duration of treatment is unknown, but it assumes an increased risk with prolonged use. Antimetabolites are carcinogenic to animals and may increase the risk of developing secondary malignant tumors in humans, albeit to a lesser extent than alkylating agents. Mercaptopurine causes chromosomal abnormalities in humans and animals and dominant lethal mutations in male rats.

    Others: hepatotoxicity or cholestasis, pancreatitis.

    Overdose:

    When an overdose is observed, a decrease in appetite, nausea, vomiting, diarrhea. Characteristic are also delayed symptoms: myelosuppression (leukopenia, thrombocytopenia and other possible complications of these conditions), a violation of liver function, gastroenteritis.

    As a treatment, it is necessary to cancel the drug, gemostimulating therapy, constant monitoring of the picture of peripheral blood and bone marrow hematopoiesis. There is no effective antagonist, hemodialysis is practically ineffective (toxic effects are mainly due to intracellularly located metabolites of the drug).

    Interaction:

    Allopurinol, colchicine, probenecid, sulfinpyrazone - possible significant increase in activity and toxicity of mercaptopurine due to inhibition of its metabolism (due to blockade of xanthine oxidase). Recommended reduction of the dose of mercaptopurine before 1/3-1/4 the usual dose with that of allopurinol 300-600 mg per day. Besides, mercaptopurine can increase the concentration of uric acid in the blood plasma, which may require correction of the dose of the antifungal drug. Combination of mercaptopurine with uricosuric antidotal drugs due to the risk of urinary acid nephropathy should be avoided.

    Anticoagulants are coumarinic or indanedic - mercaptopurine may increase anticoagulant activity and / or risk of bleeding due to inhibition of the synthesis of liver procoagulants, effects on thrombus formation, or reduction of anticoagulant activity due to increased synthesis or activation of prothrombin.

    Hepatotoxic agents: abacavir, aldesleukin, amiodarone, anabolic steroids, androgens, asparaginase, paracetamol (with long-term high-dosage therapy or acute overdose), acitretin, valproic acid, vitamin A (with chronic overdose), halothane, dantrolene, dapsone, daunorubicin, disulfiram, fat emulsions (with intravenous long-term use), iron preparations (with overdose), zidovudine, gold compounds, isoniazid, angiotensin-converting enzyme inhibitors, HMG-CoA reductase inhibitors, imatinib, itraconazole, carbamazepine, carmustine, ketoconazole (ingestion), lamivudine, mercaptopurine, methotrexate, methyldopa, naltrexone (with prolonged use in high doses), nevirapine, a nicotinic acid (when used in high doses as a hypolipidemic agent in a sustained release dosage form), nilutamide, nitrofurans, non-steroidal anti-inflammatory drugs, plikamycin, rifampicin, rosiglitazone, sulfamethoxazole + trimethoprim, sulfonamides (for systemic use), tizanidine, tolcapone, toremifene, tretinoin, phenothiazines, phenytoin, fluconazole, flutamide, cytarabine, epirubicin, erythromycin, estrogens, ethanol, ethionamide, etretinate - with simultaneous use, the risk of toxic effects increases.

    Other immunosuppressants (azathioprine, glucocorticoids, corticotropin, muroomonab, chlorambucil, ciclosporin, cyclophosphamide) - it is possible to increase the risk of infections and secondary malignant tumors with parallel application.

    Vincristine, methotrexate - mutual increase in activity and toxicity in parallel application.

    Doxorubicin is a significant increase in the risk of hepatotoxicity when applied concurrently.

    Cross-resistance of cells to mercaptopurine and thioguanine was noted.

    Methotrexate - when ingested at low doses in combination with mercaptopurine, an increase in Cmax the latter by 26%, with intravenous administration of high doses (2-5 g / m2) - by 108-121%, which has little clinical significance due to the considerable variability of the bioavailability of mercaptopurine and the lack of correlation between its plasma concentration and efficacy.

    Sulfasalazine, mesalazine, olsalazine - inhibit thiopurin methyltransferase, it is possible to increase myelotoxicity in parallel application.

    Special instructions:

    It is not recommended to apply mercaptopurine in patients with chickenpox (including recently transferred or after contact with the diseased), with herpes zoster and other acute infectious diseases. During the treatment systematically monitor the picture of peripheral blood, laboratory indicators of liver and kidney function, the level of uric acid in the blood.Do not recommend the vaccination of patients and their families. When used in patients with impaired hepatic and / or renal function, correction of the dosing regimen is required.

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