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Pyrazinamid
PYRAZINE-2-CARBOXAMIDE · PZA · Aldinamid · 2-Carbamylpyrazine · PYRAZINECARBOXAMIDE · PyrazinamidePyrazinamideBp/Usp/Ep · mk56 · PZAD
Identifikatoren & physikalische Daten
| CAS No. | 98-96-4 |
|---|---|
| Summenformel | C5H5N3O |
| Durchschnittliche Molmasse | 123,11 g/mol |
| Monoisotopische Masse | 123,04326178 g/mol |
| SMILES | NC(=O)c1cnccn1 |
| InChIKey | IPEHBUMCGVEMRF-UHFFFAOYSA-N |
| PubChem CID | 1046 |
| ChEMBL | CHEMBL614 |
| ChEBI | CHEBI:45285 |
| EC No. | 202-717-6 |
| DTXSID | DTXSID9021215 |
| Lokaler Name | Pyrazinamid |
Chemische & physikalische Eigenschaften
| XLogP | -0,6 |
|---|---|
| Polarare Oberfläche (TPSA) | 68,9 |
| H-Brücken-Donoren | 1 |
| H-Brücken-Akzeptoren | 3 |
| Frei drehbare Bindungen | 1 |
| Schwere Atome | 9 |
| Formalladung | 0 |
| Komplexität | 115 |
| Arzneimittel | Pharmaceuticals -> Listed in ZINC15 |
| pH | Aqueous solutions are neutral7 (H2O) |
| SpringerMaterials Properties | Boiling point |
| LogP (Verteilungskoeffizient) | log Kow= -0.60-1-0.5 |
| Color/Form | CrystalsCrystals from water or alcoholCrystals from water or ethyl alcohol |
| Löslichkeit | Soluble (NTP, 1992)Solubility (mg/ml, 25 °C): methanol 13.8absolute ethanol 5.7isopropanol 3.8ether 1.0isooctane 0.01chloroform 7.4In water, 15 mg/ml @ 25 °C9.37e+01 g/L>18.5 [ug/mL] (The mean of the results at pH 7.4)H2O: soluble50mg/mL |
| Human Drugs | Breast FeedingLactationMilk, HumanAnti-infective AgentsAntitubercular AgentsFDA approved drugs -> Active ingredientAntituberculosis medicines |
| Endocrine Disruptors | Potential endocrine disrupting compound |
| Siedepunkt | SUB (NTP, 1992)229.19°C (rough estimate) |
| Decomposition | When heated to decomposition it emits toxic fumes of /nitric oxides/ |
| Schmelzpunkt | 376 to 379 °F (NTP, 1992)192 °C189-191 °C (lit.) |
| Physical Description | Pyrazinamide is a white powder. Sublimes from 318 °F. (NTP, 1992)Solid |
| Dichte | 1.3260 (rough estimate) |
| Brechungsindex | 1.5900 (estimate) |
| Flammpunkt | >110°(230°F) |
| Lagerbedingungen | 2-8°C |
| Aggregatzustand | Crystalline Powder or Needles |
| pKa (Säurekonstante) | 0.5(at 25℃) |
| Farbe | White |
| Merck | 14,7956 |
| BRN | 112306 |
| BCS Class | 1,3 |
| Hauptanwendungen | pharmaceutical (small molecule) |
| InChI | 1S/C5H5N3O/c6-5(9)4-3-7-1-2-8-4/h1-3H,(H2,6,9) |
| InChIKey | IPEHBUMCGVEMRF-UHFFFAOYSA-N |
| SMILES | NC(=O)c1cnccn1 |
| LogP (Verteilungskoeffizient) | -0.600 |
| CAS Datenbank | 98-96-4(CAS DataBase Reference) |
| NIST chemische Informationen | Pyrazine carboxamide(98-96-4) |
| EPA chemische Informationen | Pyrazinamide (98-96-4) |
Sicherheit & Vorschriften
| GHS-Einstufung | This chemical does not meet GHS hazard criteria for 7.1% (4 of 56) of reports.DangerH310 (92.9%): Fatal in contact with skin [Danger Acute toxicity, dermal]P260, P262, P264, P270, P271, P280, P284, P302+P352, P304+P340, P316, P320, P321, P332+P317, P361+P364, P362+P364, P403+P233, P405, and P501 (click each P-code to see the statement)Aggregated GHS information provided per 56 reports by companies from 2 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies. |
|---|---|
| Regulatorische Informationen | Pyrazinecarboxamide: Does not have an individual approval but may be used under an appropriate group standard |
| Weitere Sicherheitsinformationen | IMAP assessments - Pyrazinecarboxamide: Environment tier I assessment |
| Gesundheitsgefahren | SYMPTOMS: Athralgias, anorexia, nausea and vomiting, dysuria, malaise and fever. |
| FDA-Anforderungen | The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl pyrazinamide, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. |
| Reaktive Gruppe | Amides and Imides |
| Reactivity Profile | PYRAZINAMIDE is an amide derivative. Incompatible with strong acids and bases, and especially incompatible with strong reducing agents such as hydrides. May react with active metals or nitrides to produce flammable gaseous hydrogen. Incompatible with strongly oxidizing acids, peroxides, and hydroperoxides. |
| Air and Water Reactions | Water soluble. |
| Hazard Classes and Categories | Acute Tox. 1 (92.9%) |
| Erste Hilfe | EYES: First check the victim for contact lenses and remove if present. Flush victim's eyes with water or normal saline solution for 20 to 30 minutes while simultaneously calling a hospital or poison control center. Do not put any ointments, oils, or medication in the victim's eyes without specific instructions from a physician. If symptoms (such as redness or irritation) develop, immediately transport the victim to a hospital. |
| Lagerbedingungen | Pyrazinamide tablets should be stored in well-closed containers at a temperature less than 40 °C, preferably between 15-30 °C. |
| Entsorgungsverfahren | SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. |
| Personal Protective Equipment (PPE) | RECOMMENDED RESPIRATOR: Where the neat test chemical is weighed and diluted, wear a NIOSH-approved half face respirator equipped with an organic vapor/acid gas cartridge (specific for organic vapors, HCl, acid gas and SO2) with a dust/mist filter. (NTP, 1992) |
| Wechselwirkungen | Pyrazinamide may increase serum uric acid concentrations and decrease the efficacy of gout therapydosage adjustments of these medications /allopurinol, colchicine, probenecid, sulfinpyrazone/ may be necessary to control hyperuricemia and gout when antigout medications are used concurrently with pyrazinamide.Concurrent use with pyrazinamide may decrease the serum concentrations of cyclosporine, possibly leading to inadequate immunosuppressioncyclosporine serum concentrations should be monitored.A 35 year old black Somalian woman with miliary tuberculosis developed hepatotoxicity after a few days of treatment with isoniazid, rifampicin, pyrazinamide, and ethambutol. After withdrawal of all drugs the liver profile returned to normal and remained so after challenge with isoniazid. Hepatotoxicity recurred when rifampicin was added, but it was well tolerated when reintroduced without isoniazid.The utility of pyrazinamide (PZA) in the short-course antituberculous treatment is well established. All available data support the idea that the PZA metabolite pyrazinoic acid (PA) is the active compound against M. tuberculosis. This situation warranted a deeper investigation of possible interactions with respect to its metabolic disposition. Caffeine, which is widely used as a drug and is a common constituent of most diets, shares with PZA the same metabolic enzyme, xanthine oxidase (XO). This study investigated if, and in what manner, concomitant administration of caffeine affects PZA metabolism. PZA and caffeine, in various doses (PZA=50 or 100 mg kg(-1) and caffeine= 0, 50, 100, and 150 mg kg(-1)), were administered to female Sprague-Dawley rats. PZA and its three main metabolites were quantified in 24 h urine samples by reversed phase-HPLC Concomitant administration of 100 mg kg(-1) caffeine and 50 mg kg(-1) PZA increased from the excretion (p<0.05) of the most water-soluble and the least toxic PZA metabolite 5-hydroxypyrazinoic acid (5-OH-PA) from 66.18+/-10.87 to 94.56+/-8.65 micromol/24 h. This effect was more pronounced when 100 mg kg(-1) of PZA was administered increasing excretion of 5-OH-PA from 113.28+/-70 to 173.23+/-17.82 micromol/24 h. These results show that the metabolic disposition of PZA is affected by concomitant caffeine intake.For more Interactions (Complete) data for PYRAZINAMIDE (9 total), please visit the HSDB record page. |
| Hepatotoxicity | Combination therapy for tuberculosis using pyrazinamide is commonly associated with transient and asymptomatic elevations in the serum aminotransferase levels. These elevations are usually less than five times the upper limit of the normal range. Because pyrazinamide is used only in combination with other antituberculosis medications, its contributions to serum enzyme elevations is not completely clear, but it is frequently incriminated in transient serum enzyme elevations. Clinically apparent liver disease with symptoms and jaundice also occur with pyrazinamide therapy and it is often considered the culprit in causing liver injury in the face of double or triple antituberculosis therapy (Case 1). Indeed, the use of a short, 2 month course of combination therapy with rifampin and pyrazinamide for latent tuberculosis was abandoned because of the frequency of severe liver injury with this regimen that was occasionally fatal (Case 2). The onset of injury due to pyrazinamide is generally after 4 to 8 weeks and occasionally becomes apparent only after the pyrazinamide is stopped. The pattern of liver enzyme elevations is typically hepatocellular and the clinical syndrome resembles acute viral hepatitis, much like isoniazid hepatotoxicity. Features of hypersensitivity (rash, fever and eosinophilia) are uncommon as are autoantibody formation. Liver biopsy demonstrates changes typical of acute hepatitis with portal and lobular inflammation, hepatocellular necrosis and variable degrees of cholestasis. |
| Ongoing Test Status | The following link will take the user to the National Toxicology Program (NTP) Test Agent Search Results page, which tabulates all of the "Standard Toxicology & Carcinogenesis Studies", "Developmental Studies", and "Genetic Toxicity Studies" performed with this chemical. Clicking on the "Testing Status" link will take the user to the status (i.e., in review, in progress, in preparation, on test, completed, etc.) and results of all the studies that the NTP has done on this chemical. [http://ntp-apps.niehs.nih.gov/ntp_tox/index.cfm?fuseaction=ntpsearch.searchresults&searchterm=98-96-4] |
| Human Toxicity Excerpts | /SPECIAL STUDIES/ Cytogenetic analyses were carried out in lymphocytes of 15 untreated tuberculosis (tb) patients and 15 other tb patients who had received combined tuberculostatic chemotherapy HRZ (isoniazid + rifampicin + pyrazinamide) for 2 months. The frequency of chromosomal aberrations and sister chromatid exchanges (SCEs) did not show any statistically significant differences in the patients before treatment and after exposure to combined HRZ therapy as compared to controls (p > 0.051. However, /it was/ observed that the mitotic index was significantly decr in both groups (p < 0.05). |
| Carcinogen Classification | PyrazinamideTR-048: Bioassay of Pyrazinamide for Possible Carcinogenicity (CASRN 98-96-4) (1978 )01/18/78No Evidence |
| Drug Induced Liver Injury | Drug Induced Liver Injury Rank (DILIrank 2.0)PyrazinamidevLess-DILI-concern3Warnings & precautionsDOI:10.1016/j.drudis.2016.02.015 |
| Non-Human Toxicity Excerpts | /LABORATORY ANIMALS: Acute Exposure/ Moderately toxic by ingestion, subcutaneous, and intraperitoneal routes./LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Pyrazinamide reportedly was not carcinogenic in rats or male mice (as determined in lifetime bioassays) when administered in daily doses of approximately 10-40 times the maximum recommended human doseresults in female mice could not be determined because of insufficient numbers of surviving mice in the control group./LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ We have tested Pyrazinamide (PZA), an essential component of modern short-course tuberculosis treatment regimen, for teratogenicity using Wistar rats. The drug was given by oral intubation from 6-15 days of gestation, at doses of 0, 25, 100 and 500 mg/kg body weight per day. Reduction in body weight and food consumption were observed in the treated dams. On day 20 of gestation, all the dams were killed by cervical dislocation and signs of maternal toxicity, reproductive indices and fetal measurements were recorded. Dams given doses of 100 and 500 mg/kg had significantly higher incidence of reabsorbed fetuses, reduced litter size, and impaired neonatal growth than those given no PZA or only 25 mg/kg dose. External visceral and skeletal examination of all fetuses of PZA-treated dams showed several types of variations which were neither dose related nor having a consistent pattern. However, these variations occurred mostly in the dams treated with the dose of 500 mg/kg. In conclusion, these data show that in Wistar rats, only high doses of PZA (100 and 500 mg/kg) produced fetotoxicity. No evidence of teratogenic effect of the drug was observed./GENOTOXICITY/ Pyrazinamide ...did induce chromosomal aberrations in human lymphocyte cell cultures.For more Non-Human Toxicity Excerpts (Complete) data for PYRAZINAMIDE (7 total), please visit the HSDB record page. |
| National Toxicology Program Studies | A bioassay of the tuberculostatic drug pyrazinamide for possible carcinogenicity was conducted by administering the test chemical in feed to Fischer 344 rats and B6C3F1 mice. Groups of 35 rats and 35 mice of each sex were administered pyrazinamide at one of two doses, either 5,000 or 10,000 ppm, for 78 weeks, and then observed for an additional 26 or 27 weeks. Matched controls consisted of groups of 15 untreated rats and 15 untreated mice of each sex. High-dose male mice died or were killed by week 92all other surviving animals were killed at weeks 104 or 105. Mean body weights of the dosed male rats were slightly lower than those of the matched controls, while mean body weights of the dosed females were more nearly comparable to those of the controls. A sufficient number of rats in each group was at risk to termination of the study at weeks 104-105 for the development of late-appearing tumors. In mice, administration of pyrazinamide had no consistent effect on mean body weights. Survival to termination of the study was low, particularly among the control groups. In rats, no lesions could clearly be related to administration of the chemical. In mice, interstitial and suppurative myocarditis in the dosed animals and suppurative bronchopneumonias in both dosed and matched control mice of each sex were associated with increased deaths. In the females, there was a significant positive dose-related trend (P=0.037) in the incidence of lymphoma (matched controls 0/13, low-dose 2/25, high-dose 6/29)however, the incidences in each of the dosed groups were not significant when compared with that in the matched controls. In addition, the poor survival and the small size of the control group precluded making a clear association of the incidence of these tumors with administration of the chemical. It is concluded that under the conditions of this bioassay, the early deaths and small size of the control group precluded a conclusion regarding the carcinogenicity of pyrazinamide in female B6C3F1 mice. Pyrazinamide was not carcinogenic for Fischer 344 rats or for male mice. |
| Effects During Pregnancy and Lactation | ◉ Summary of Use during Lactation |
| Non-Human Toxicity Values | LDLo Rat oral 3 g/kgLDLo Mouse oral 3 g/kgLD50 Mouse intraperitoneal 1680 mg/kgLD50 Mouse subcutaneous 2793 mg/kg |
| Wassergefährdungsklasse (WGK) | 3 |
| TSCA-Inventar-Status | TSCA listed |
| Zollcode | 29339990 |
| RTECS-Nr. | UQ2275000 |
| R-Sätze (R) | 11-34 |
| Toxizität | LD50 intraperitoneal in mouse: 1680mg/kg |
| Gefahrensymbole | F,C |
| Sicherheitshinweise (S) | 22-24/25-45-36/37/39-26-16 |
| Lagerklasse | 11 - Combustible Solids |
| Gefahrstoffdaten | 98-96-4(Hazardous Substances Data) |
Anwendungen & Verwendung
Beschreibung
Pyrazinamide was synthesized in 1952, and it is the nitrogen-analog of nicotinamide. It exhibits hepatotoxicity. Synonyms of this drug are dexambutol, miambutol, esnbutol, ebutol, and others.
Verwenden
Pyrazinamide is used therapeutically as an antitubercular agent. Pyrazinamide is used to form polymeric copper complexes, create pyrazine carboxamide scaffolds useful as FXs inhibitors, and as a component of mycobacteria identification kits. It is used to study liver toxicity prevention and mechanisms of resistance .