6-머캡토퓨린

Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide. /6-Mercaptopurine monohydrate/

Advice for firefighters: Wear self contained breathing apparatus for fire fighting if necessary. /6-Mercaptopurine monohydrate/

Store at 20 deg to 25 °C (68 deg to 77 °F). Store in a dry place.

Keep container tightly closed in a dry and well-ventilated place. /6-Mercaptopurine monohydrate/

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Use personal protective equipment. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Evacuate personnel to safe areas. Avoid breathing dust. Environmental precautions: Do not let product enter drains. Methods and materials for containment and cleaning up: Pick up and arrange disposal without creating dust. Sweep up and shovel. Keep in suitable, closed containers for disposal. /6-Mercaptopurine monohydrate/

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

Product: Offer surplus and non-recyclable solutions to a licensed disposal company. Contact a licensed professional waste disposal service to dispose of this material. Dissolve or mix the material with a combustible solvent and burn in a chemical incinerator equipped with an afterburner and scrubber; Contaminated packaging: Dispose of as unused product. /6-Mercaptopurine monohydrate/

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Use personal protective equipment. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Evacuate personnel to safe areas. Avoid breathing dust. Environmental precautions: Do not let product enter drains. /6-Mercaptopurine monohydrate/

Precautions for safe handling: Avoid contact with skin and eyes. Avoid formation of dust and aerosols. Provide appropriate exhaust ventilation at places where dust is formed. Normal measures for preventive fire protection. /6-Mercaptopurine monohydrate/

Appropriate engineering controls: Handle in accordance with good industrial hygiene and safety practice. Wash hands before breaks and at the end of workday. /6-Mercaptopurine monohydrate/

Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands. /6-Mercaptopurine monohydrate/

SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker.

Eye/face protection: Safety glasses with side-shields conforming to EN166. Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU). /6-Mercaptopurine monohydrate/

Skin protection: Handle with gloves. /6-Mercaptopurine monohydrate/

Body Protection: Complete suit protecting against chemicals. The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace. /6-Mercaptopurine monohydrate/

Respiratory protection: For nuisance exposures use type P95 (US) or type P1 (EU EN 143) particle respirator. For higher level protection use type OV/AG/P99 (US) or type ABEK-P2 (EU EN 143) respirator cartridges. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU). /6-Mercaptopurine monohydrate/

Mercaptopurine is a purine analog used for acute lymphoblatic leukemia and chronic myelogenous leukemias. Since it is inactivated by xanthine oxidase (XO), concurrent intake of substances containing XO may potentially reduce bioavailability of mercaptopurine. Cow's milk is known to contain a high level of XO. In vitro and in vivo data suggest that concurrent intake of cow's milk may reduce the bioavailability of mercaptopurine. This interaction may be clinically significant. Therefore most patients should try to separate the timing of taking mercaptopurine and drinking milk.

The dosage of mercaptopurine may need to be reduced when the drug is used concomitantly with other drugs that cause myelosuppression. Exacerbation of myelosuppression associated with mercaptopurine has been observed in patients receiving trimethoprim-sulfamethoxazole.

As there is in vitro evidence that aminosalicylate derivatives (e.g., olsalazine, mesalamine, or sulfasalazine) inhibit the TPMT /thiopurine-S-methyltransferase/ enzyme, they should be administered with caution to patients receiving concurrent mercaptopurine therapy.

In dosages of 300-600 mg daily, allopurinol inhibits the oxidative metabolism of mercaptopurine by xanthine oxidase, thus increasing the possibility of toxic effects of mercaptopurine, particularly bone marrow depression. If allopurinol and mercaptopurine are administered concomitantly, the dosage of mercaptopurine should be reduced to 25-33% of the usual dosage, and subsequent dosage adjusted according to the patient response and toxic effects.

For more Interactions (Complete) data for Mercaptopurine (11 total), please visit the HSDB record page.

Mercaptopurine has been associated with several forms of hepatotoxicity. Patients receiving mercaptopurine for leukemia often have transient and asymptomatic rises in serum aminotransferase or alkaline phosphatase levels and a proportion of these patients develop jaundice, particularly when it is given in high doses. In case series of patients with autoimmune diseases (such as inflammatory bowel disease) treated with mercaptopurine, up to 30% developed serum aminotransferase elevations and these can be persistent as long as therapy is continued, resolving either with dose reduction or discontinuation. Liver biopsy usually demonstrates steatosis and centrolobular injury with scant inflammation.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 89(SRC), determined from a structure estimation method(2), indicates that mercaptopurine is expected to have high mobility in soil(SRC). Volatilization of mercaptopurine from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 7.5X10-10 atm-cu m/mole(SRC), using a fragment constant estimation method(3). Mercaptopurine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.3X10-8 mm Hg(SRC), determined from a fragment constant method(2). Biodegradation data in soil were not available(SRC, 2016).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 89(SRC), determined from a structure estimation method(2), indicates that mercaptopurine is not expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 7.5X10-10 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 3(SRC), from its log Kow of 0.01(6) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation data in water were not available(SRC, 2016).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), mercaptopurine, which has an estimated vapor pressure of 1.3X10-8 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase mercaptopurine is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 0.05 days(SRC), calculated from its rate constant of 2.0X10-10 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(3). Particulate-phase mercaptopurine may be removed from the air by wet and dry deposition(SRC). Mercaptopurine absorbs UV light at wavelengths >290 nm(4) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

Patients may exhibit non-dose dependent or dose-dependent side effects while undergoing treatment with mercaptopurine. Allergic reactions such as nausea, fever, rash, flu-like symptoms, and arthralgias are considered non-dose-dependent symptoms that may require changing the timing of dosing to night-time administration or discontinuation of therapy.

IDENTIFICATION AND USE: Mercaptopurine is an antineoplastic agent. It is indicated for maintenance therapy of acute lymphatic (lymphocytic, lymphoblastic) leukemia as part of a combination regimen. It may have potential benefit in treating other autoimmune conditions (eg, unresponsive ulcerative colitis) as well. Veterinary uses of mercaptopurine have included adjunctive therapy of lymphosarcoma, acute leukemias, and severe rheumatoid arthritis. HUMAN EXPOSURE AND TOXICITY: Signs and symptoms of overdosage may be immediate (anorexia, nausea, vomiting, and diarrhea); or delayed (myelosuppression, liver dysfunction, and gastroenteritis). Dialysis cannot be expected to clear mercaptopurine. Hemodialysis is thought to be of marginal use due to the rapid intracellular incorporation of mercaptopurine into active metabolites with long persistence. Hepatosplenic T-cell lymphoma, a rare, aggressive, usually fatal type of T-cell lymphoma, has been reported during postmarketing experience mainly in adolescents and young adults with Crohn's disease or ulcerative colitis who received treatment with thiopurine analogs (mercaptopurine or azathioprine) and/or tumor necrosis factor (TNF) blocking agents. Although most of the reported cases occurred in patients who had received a combination of immunosuppressive agents, including TNF blocking agents and thiopurine analogs (mercaptopurine or azathioprine), cases have been reported in patients receiving mercaptopurine or azathioprine alone. Hepatotoxicity manifested by rapid onset of jaundice, cholestasis, ascites, hepatic encephalopathy, and/or elevated hepatic enzyme concentrations, usually associated with hepatic necrosis and severe fibrosis, may occur in patients receiving mercaptopurine; deaths from hepatic necrosis have occurred. In some cases, hepatotoxicity has been associated with anorexia and diarrhea. Hepatic function must be carefully monitored in patients receiving mercaptopurine. Although hepatic injury can occur at any dosage, the incidence appears to increase when dosage exceeds 2.5 mg/kg daily. The most consistent dose-dependent toxicity of mercaptopurine is myelosuppression manifested by anemia, leukopenia, thrombocytopenia, or any combination of these effects. These findings also may reflect progression of disease. Life-threatening infection and bleeding have occurred in patients with mercaptopurine-induced granulocytopenia and thrombocytopenia, respectively. Increases in chromosomal aberrations were found in human peripheral lymphocytes exposed in vitro. ANIMAL STUDIES: After a single lethal dose of mercaptopurine, the majority of rats survive 2 - 3 days, and deaths do not occur in mice until at least 5 days after injection. In rats, early deaths are due to lung damage, a toxic effect not seen in other species such as mouse, cat or dog. ln rats and mice, the predominant toxicity of 6-MP is damage to the bone-marrow and intestinal epithelium and hepatic necrosis. Major toxic symptoms in dogs were marked damage to the small intestinal mucosa and bone-marrow depletion. Biochemical evidence of liver damage was present, and jaundice was apparent in treated animals, although livers had only relatively insignificant microscopic foci of necrosis. Doses of 20, 10 or 5 mg/kg bw mercaptopurine plus the same doses of 6-methylmercaptopurine riboside were reported to increase the incidence of Iymphoreticular tumors in mice. No such effect was seen in rats given 6 or 3 mg/kg bw of each drug. Female mice were treated subcutaneously with 3 mg/kg bw 6-mercaptopurine daily, starting 3 days before mating with untreated males and up through day 18 of pregnancy. Many of the surviving female offspring, although they had normal body weight, development and general appearance, were either sterile or, if they became pregnant, had smaller litters and more dead fetuses as compared with controls. Histological study of the ovaries of offspring exposed to 6-mercaptopurine in utero revealed that there were few oocytes and ovarian follicles; many ovaries were completely devoid of oocytes. Mercaptopurine induced apoptotic cell death in neural cells in the rat fetal brain. Long-term mercaptopurine treatment in male mice did not impair sperm production and sperm morphology. However, a significantly high rate of embryonic resorption indicated occult sperm damage. Mercaptopurine produced dominant lethal effects in vivo in the premeiotic and early meiotic germ cells of male mice and an increase in the number of micronuclei in mouse bone marrow. Chromosomal aberrations were observed in the bone-marrow cells of rats and Chinese hamsters following ip administration of 6-mercaptopurine and in mice after oral or parenteral administration. Mercaptopurine was mutagenic without metabolic activation in Salmonella typhimurium tester strains his G46 and TA 1535.

EPA has released the Interactive Chemical Safety for Sustainability (iCSS) Dashboard. The iCSS Dashboard provides an interactive tool to explore rapid, automated (or in vitro high-throughput) chemical screening data generated by the Toxicity Forecaster (ToxCast) project and the federal Toxicity Testing in the 21st century (Tox21) collaboration. /The title compound was tested by ToxCast and/or Tox21 assays/[USEPA; ICSS Dashboard Application; Available from, as of December 8, 2016: http://actor.epa.gov/dashboard/]

The following link will take the user to the National Toxicology Program (NTP) Test Status of Agents Search page, which tabulates the results and current status of tests such as "Short-Term Toxicity Studies", "Long-term Carcinogenicity Studies", "Developmental Studies", "Genetic Toxicology Studies", etc., performed with this chemical. Testing status for mercaptopurine is available.[Available from, as of March 24, 2017: https://ntpsearch.niehs.nih.gov/?e=True&ContentType=Testing+Status]

Using a structure estimation method based on molecular connectivity indices(1), the Koc of mercaptopurine can be estimated to be 89(SRC). According to a classification scheme(2), this estimated Koc value suggests that mercaptopurine is expected to have high mobility in soil.

/SIGNS AND SYMPTOMS/ Signs and symptoms of overdosage may be immediate (anorexia, nausea, vomiting, and diarrhea); or delayed (myelosuppression, liver dysfunction, and gastroenteritis). Dialysis cannot be expected to clear mercaptopurine. Hemodialysis is thought to be of marginal use due to the rapid intracellular incorporation of mercaptopurine into active metabolites with long persistence.

/SIGNS AND SYMPTOMS/ Hepatosplenic T-cell lymphoma, a rare, aggressive, usually fatal type of T-cell lymphoma, has been reported during postmarketing experience mainly in adolescents and young adults with Crohn's disease or ulcerative colitis who received treatment with thiopurine analogs (mercaptopurine or azathioprine) and/or tumor necrosis factor (TNF) blocking agents. Although most of the reported cases occurred in patients who had received a combination of immunosuppressive agents, including TNF blocking agents and thiopurine analogs (mercaptopurine or azathioprine), cases have been reported in patients receiving mercaptopurine or azathioprine alone.

/SIGNS AND SYMPTOMS/ Hepatotoxicity manifested by rapid onset of jaundice, cholestasis, ascites, hepatic encephalopathy, and/or elevated hepatic enzyme concentrations, usually associated with hepatic necrosis and severe fibrosis, may occur in patients receiving mercaptopurine; deaths from hepatic necrosis have occurred. In some cases, hepatotoxicity has been associated with anorexia and diarrhea. Hepatic function must be carefully monitored in patients receiving mercaptopurine. Although hepatic injury can occur at any dosage, the incidence appears to increase when dosage exceeds 2.5 mg/kg daily.

/SIGNS AND SYMPTOMS/ The most consistent dose-dependent toxicity of mercaptopurine is myelosuppression manifested by anemia, leukopenia, thrombocytopenia, or any combination of these effects. These findings also may reflect progression of disease. Life-threatening infection and bleeding have occurred in patients with mercaptopurine-induced granulocytopenia and thrombocytopenia, respectively.

For more Human Toxicity Excerpts (Complete) data for Mercaptopurine (15 total), please visit the HSDB record page.

Mercaptopurine's production and administration as an antineoplastic, anti-inflammatory for specific disorders and immunosuppressant in organ transplant patients(1) may result in its release to the environment through various waste streams(SRC).

6-Mercaptopurine

Group 3: Not classifiable as to its carcinogenicity to humans

Volume 26: (1981) Some Antineoplastic and Immunosuppressive Agents

1987

1987

Drug Induced Liver Injury Rank (DILIrank 2.0)

Mercaptopurine

vMost-DILI-concern

8

Warnings & precautions

DOI:10.1016/j.drudis.2016.02.015

An estimated BCF of 3 was calculated in fish for mercaptopurine(SRC), using a log Kow of 0.01(1) and a regression-derived equation(1). According to a classification scheme(2), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including mercaptopurine, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

MEDICATION

MEDICATION (VET)

Mercaptopurine tablets are indicated for maintenance therapy of acute lymphatic (lymphocytic, lymophoblastic) leukemia as part of a combination regimen. The response to this agent depends upon the particular subclassification of acute lymphatic leukemia and the age of the patient (pediatric or adult). Mercaptopurine is not effective prophylaxis or treatment of central nervous system leukemia. Mercaptopurine is not effective in acute myelogenous leukemia, chronic lymphatic leukemia, the lymphomas (including Hodgkins Disease), or solid tumors. /Included in US product label/

MEDICATION (VET): Rarely used in veterinary medicine. Veterinary uses of mercaptopurine have included adjunctive therapy of lymphosarcoma, acute leukemias, and severe rheumatoid arthritis. It may have potential benefit in treating other autoimmune conditions (eg, unresponsive ulcerative colitis) as well.

Antimetabolites; Antimetabolites, Antineoplastic; Immunosuppressive Agents; Nucleic Acid Synthesis Inhibitors

In the original and most simple synthesis, hypoxanthine is heated with an excess of phosphorous pentasulfide for several hours at 200 °C in, e.g., tetralin as the solvent.

Preparation from 7-aminothiazolo[5,4-d]pyrimidine: G. H. Hitchings, G. B. Elion, United States of America patent 2721866 (1955 to Burroughs Wellcome).

6-Chloropurine + sodium thiocyanate (dehydrochlorination) thiocyanate hydrolysis