Pyrazinamide
Identification
- Name
- Pyrazinamide
- Accession Number
- DB00339 (APRD01206)
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Description
A pyrazine that is used therapeutically as an antitubercular agent.
- Structure
Structure for Pyrazinamide (DB00339)
- Synonyms
- 2-carbamylpyrazine
- 2-pyrazinecarboxamide
- Aldinamide
- Pirazinamida
- Pirazinamide
- Pyrazinamid
- Pyrazinamida
- Pyrazinamide
- Pyrazinamidum
- Pyrazine carboxamide
- pyrazine-2-carboxamide
- Pyrazineamide
- Pyrazinecarboxamide
- Pyrazinoic acid amide
- Pyrizinamide
- External IDs
- D-50 / MK-56 / NSC-14911 / PZA
- Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Unlock Additional DataTebrazid Tablet Oral Valeant Canada Lp Valeant Canada S.E.C. 1973-12-31 Not applicable Canada 
Additional Data Available- Application NumberApplication Number
A unique ID assigned by the FDA when a product is submitted for approval by the labeller.
Learn more - Product CodeProduct Code
A governmentally-recognized ID which uniquely identifies the product within its regulatory market.
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- Generic Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Unlock Additional DataPdp-pyrazinamide Tablet Oral Pendopharm Division Of Pharmascience Inc 1984-12-31 Not applicable Canada Pyrazinamide Tablet 500 mg/1 Oral American Health Packaging 2016-10-24 Not applicable US 
Pyrazinamide Tablet 500 mg/1 Oral Physicians Total Care, Inc. 1971-06-03 2003-06-30 US Pyrazinamide Tablet 500 mg/1 Oral A-S Medication Solutions 1995-04-01 Not applicable US Pyrazinamide Tablet 500 mg/1 Oral VersaPharm Inc. - an Akorn Company 1995-04-01 Not applicable US Pyrazinamide Tablet 500 mg/1 Oral Clinical Solutions Wholsesale 1971-06-03 2017-06-15 US Pyrazinamide Tablet 500 mg/1 Oral A-S Medication Solutions 1971-06-03 Not applicable US Pyrazinamide Tablet 500 mg/1 Oral Remedy Repack 2015-06-26 2016-06-26 US Pyrazinamide Tablet 500 mg/1 Oral Remedy Repack 2008-05-21 2018-10-23 US Pyrazinamide Tablet 500 mg/1 Oral Mikart, Inc. 1992-06-30 2016-08-26 US Additional Data Available- Application NumberApplication Number
A unique ID assigned by the FDA when a product is submitted for approval by the labeller.
Learn more - Product CodeProduct Code
A governmentally-recognized ID which uniquely identifies the product within its regulatory market.
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- Mixture Products
Name Ingredients Dosage Route Labeller Marketing Start Marketing End Rifater Pyrazinamide (300 mg/1) + Isoniazid (50 mg/1) + Rifampicin (120 mg/1) Tablet, sugar coated Oral Remedy Repack 2010-09-15 2010-09-16 US Rifater Pyrazinamide (300 mg) + Isoniazid (50 mg) + Rifampicin (120 mg) Tablet Oral Sanofi Aventis 1995-12-31 2017-03-29 Canada Rifater Pyrazinamide (300 mg/1) + Isoniazid (50 mg/1) + Rifampicin (120 mg/1) Tablet, sugar coated Oral sanofi-aventis U.S. LLC 1994-05-31 Not applicable US - International/Other Brands
- Piraldina (Bracco) / Prazina (Armoxindo) / Pyrafat (Riemser) / Pyrazide (Sanofi-Aventis) / Tebrazid (Valeant) / Tisamid (Orion)
- Categories
- UNII
- 2KNI5N06TI
- CAS number
- 98-96-4
- Weight
- Average: 123.1127
Monoisotopic: 123.043261797 - Chemical Formula
- C5H5N3O
- InChI Key
- IPEHBUMCGVEMRF-UHFFFAOYSA-N
- InChI
- InChI=1S/C5H5N3O/c6-5(9)4-3-7-1-2-8-4/h1-3H,(H2,6,9)
- IUPAC Name
- pyrazine-2-carboxamide
- SMILES
- NC(=O)C1=NC=CN=C1
Pharmacology
- Indication
For the initial treatment of active tuberculosis in adults and children when combined with other antituberculous agents.
- Associated Conditions
- Pharmacodynamics
Pyrazinamide kills or stops the growth of certain bacteria that cause tuberculosis (TB). It is used with other drugs to treat tuberculosis. It is a highly specific agent and is active only against Mycobacterium tuberculosis. In vitro and in vivo, the drug is active only at a slightly acid pH. Pyrazinamie gets activated to Pyrazinoic acid in the bacilli where it interferes with fatty acid synthase FAS I. This interferes with the bacteriums ability to synthesize new fatty acids, required for growth and replication.
- Mechanism of action
Pyrazinamide diffuses into active M. tuberculosis that express pyrazinamidase enzyme that converts pyrazinamide to the active form pyrazinoic acid. Pyrazinoic acid can leak out under acidic conditions to be converted to the protonated conjugate acid, which is readily diffused back into the bacilli and accumulate intracellularly. The net effect is that more pyrazinoic acid accumulates inside the bacillus at acid pH than at neutral pH. Pyrazinoic acid was thought to inhibit the enzyme fatty acid synthase (FAS) I, which is required by the bacterium to synthesise fatty acids. However, this theory was thought to have been discounted.5 However, further studies reproduced the results of FAS I inhibition as the putative mechanism first in whole cell assay of replicating M. tuberculosis bacilli which have shown that pyrazinoic acid and its ester inhibit the synthesis of fatty acids.6 This study was followed by in vitro assay of tuberculous FAS I enzyme that tested the activity with pyrazinamide, pyrazinoic acid and several classes of pyrazinamide analogs. Pyrazinamide and its analogs inhibited the activity of purified FAS I.7
It has also been suggested that the accumulation of pyrazinoic acid disrupts membrane potential and interferes with energy production, necessary for survival of M. tuberculosis at an acidic site of infection. Pyrazinoic acid has also been shown to bind to the ribosomal protein S1 (RpsA) and inhibit trans-translation. This may explain the ability of the drug to kill dormant mycobacteria.8
Target Actions Organism AFatty acid synthetase inhibitorMycobacterium tuberculosis (strain ATCC 25618 / H37Rv) - Absorption
Rapidly and well absorbed from the gastrointestinal tract.
- Volume of distribution
- Not Available
- Protein binding
~10% (bound to plasma proteins)
- Metabolism
Hepatic.
- Route of elimination
Approximately 70% of an oral dose is excreted in the urine, mainly by glomerular filtration within 24 hours
- Half life
9-10 hours (normal conditions)
- Clearance
- Not Available
- Toxicity
Side effects include liver injury, arthralgias, anorexia, nausea and vomiting, dysuria,malaise and fever, sideroblastic anemia, adverse effects on the blood clotting mechanism or vascular integrity, and hypersensitivity reactions such as urticaria, pruritis and skin rashes.
- Affected organisms
- Mycobacterium tuberculosis
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Comprehensive structured data on known drug adverse effects with statistical prevalence. MedDRA and ICD10 ids are provided for adverse effect conditions and symptoms.
Learn moreStructured data covering drug contraindications. Each contraindication describes a scenario in which the drug is not to be used. Includes restrictions on co-administration, contraindicated populations, and more.
Learn moreStructured data representing warnings from the black box section of drug labels. These warnings cover important and dangerous risks, contraindications, or adverse effects.
Learn moreInteractions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Unlock Additional Data(R)-warfarin The risk or severity of bleeding can be increased when Pyrazinamide is combined with (R)-warfarin. (S)-Warfarin The risk or severity of bleeding can be increased when Pyrazinamide is combined with (S)-Warfarin. 4-hydroxycoumarin The risk or severity of bleeding can be increased when Pyrazinamide is combined with 4-hydroxycoumarin. Abacavir Pyrazinamide may decrease the excretion rate of Abacavir which could result in a higher serum level. Acarbose Acarbose may decrease the excretion rate of Pyrazinamide which could result in a higher serum level. Aceclofenac Aceclofenac may decrease the excretion rate of Pyrazinamide which could result in a higher serum level. Acemetacin Acemetacin may decrease the excretion rate of Pyrazinamide which could result in a higher serum level. Acenocoumarol The risk or severity of bleeding can be increased when Pyrazinamide is combined with Acenocoumarol. Acetaminophen Acetaminophen may decrease the excretion rate of Pyrazinamide which could result in a higher serum level. Acetazolamide Acetazolamide may increase the excretion rate of Pyrazinamide which could result in a lower serum level and potentially a reduction in efficacy. Additional Data Available- Extended DescriptionExtended Description
Extended description of the mechanism of action and particular properties of each drug interaction.
Learn more - Severity
- Evidence Level
- ActionAction
An effect category for each drug interaction. Know how this interaction affects the subject drug.
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- Food Interactions
- Take with or without food. The absorption is unaffected by food.
References
- General References
- Authors unspecified: Controlled trial of four thrice-weekly regimens and a daily regimen all given for 6 months for pulmonary tuberculosis. Lancet. 1981 Jan 24;1(8213):171-4. [PubMed:6109855]
- Authors unspecified: Controlled clinical trial of 4 short-couse regimens of chemotherapy (three 6-month and one 8-month) for pulmonary tuberculosis. Tubercle. 1983 Sep;64(3):153-66. [PubMed:6356538]
- Authors unspecified: A controlled trial of 6 months' chemotherapy in pulmonary tuberculosis. Final report: results during the 36 months after the end of chemotherapy and beyond. British Thoracic Society. Br J Dis Chest. 1984 Oct;78(4):330-6. [PubMed:6386028]
- Yee D, Valiquette C, Pelletier M, Parisien I, Rocher I, Menzies D: Incidence of serious side effects from first-line antituberculosis drugs among patients treated for active tuberculosis. Am J Respir Crit Care Med. 2003 Jun 1;167(11):1472-7. Epub 2003 Jan 31. [PubMed:12569078]
- Boshoff HI, Mizrahi V, Barry CE 3rd: Effects of pyrazinamide on fatty acid synthesis by whole mycobacterial cells and purified fatty acid synthase I. J Bacteriol. 2002 Apr;184(8):2167-72. [PubMed:11914348]
- Zimhony O, Vilcheze C, Arai M, Welch JT, Jacobs WR Jr: Pyrazinoic acid and its n-propyl ester inhibit fatty acid synthase type I in replicating tubercle bacilli. Antimicrob Agents Chemother. 2007 Feb;51(2):752-4. Epub 2006 Nov 13. [PubMed:17101678]
- Ngo SC, Zimhony O, Chung WJ, Sayahi H, Jacobs WR Jr, Welch JT: Inhibition of isolated Mycobacterium tuberculosis fatty acid synthase I by pyrazinamide analogs. Antimicrob Agents Chemother. 2007 Jul;51(7):2430-5. Epub 2007 May 7. [PubMed:17485499]
- Shi W, Zhang X, Jiang X, Yuan H, Lee JS, Barry CE 3rd, Wang H, Zhang W, Zhang Y: Pyrazinamide inhibits trans-translation in Mycobacterium tuberculosis. Science. 2011 Sep 16;333(6049):1630-2. doi: 10.1126/science.1208813. Epub 2011 Aug 11. [PubMed:21835980]
- External Links
- Human Metabolome Database
- HMDB0014483
- KEGG Drug
- D00144
- KEGG Compound
- C01956
- PubChem Compound
- 1046
- PubChem Substance
- 46507478
- ChemSpider
- 1017
- BindingDB
- 228814
- RxNav
- 8987
- ChEBI
- 45285
- ChEMBL
- CHEMBL614
- ZINC
- ZINC000000002005
- Therapeutic Targets Database
- DAP000660
- PharmGKB
- PA451182
- PDBe Ligand
- PZA
- RxList
- RxList Drug Page
- Drugs.com
- Drugs.com Drug Page
- Wikipedia
- Pyrazinamide
- ATC Codes
- J04AK01 — Pyrazinamide
- J04AK — Other drugs for treatment of tuberculosis
- J04A — DRUGS FOR TREATMENT OF TUBERCULOSIS
- J04 — ANTIMYCOBACTERIALS
- J — ANTIINFECTIVES FOR SYSTEMIC USE
- J04AM — Combinations of drugs for treatment of tuberculosis
- J04A — DRUGS FOR TREATMENT OF TUBERCULOSIS
- J04 — ANTIMYCOBACTERIALS
- J — ANTIINFECTIVES FOR SYSTEMIC USE
- AHFS Codes
- 08:16.04 — Antituberculosis Agents
- PDB Entries
- 3r4x / 3r55 / 5fpd
- MSDS
- Download (73.6 KB)
Clinical Trials
- Clinical Trials
Pharmacoeconomics
- Manufacturers
- Dava pharmaceuticals inc
- Mikart inc
- Packagers
- Amerisource Health Services Corp.
- A-S Medication Solutions LLC
- Belgomex Sprl
- Cardinal Health
- Comprehensive Consultant Services Inc.
- DAVA Pharmaceuticals
- Dept Health Central Pharmacy
- Mikart Inc.
- Murfreesboro Pharmaceutical Nursing Supply
- PCA LLC
- PD-Rx Pharmaceuticals Inc.
- Physicians Total Care Inc.
- Prescript Pharmaceuticals
- Remedy Repack
- Sanofi-Aventis Inc.
- Versapharm Inc.
- West-Ward Pharmaceuticals
- Dosage forms
Form Route Strength Tablet Oral Tablet Oral 500 mg/1 Tablet Oral Tablet, sugar coated Oral - Prices
Unit description Cost Unit Rifater tablet 3.1USD tablet Pyrazinamide 500 mg tablet 1.26USD tablet DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.- Patents
- Not Available
Properties
- State
- Solid
- Experimental Properties
Property Value Source melting point (°C) 192 °C PhysProp water solubility 1.5E+004 mg/L (at 25 °C) MERCK INDEX (1996) logP -0.60 HANSCH,C ET AL. (1995) logS -0.91 ADME Research, USCD pKa -0.5 Not Available - Predicted Properties
Property Value Source Water Solubility 93.7 mg/mL ALOGPS logP -0.71 ALOGPS logP -1.2 ChemAxon logS -0.12 ALOGPS pKa (Strongest Acidic) 13.06 ChemAxon pKa (Strongest Basic) -0.68 ChemAxon Physiological Charge 0 ChemAxon Hydrogen Acceptor Count 3 ChemAxon Hydrogen Donor Count 1 ChemAxon Polar Surface Area 68.87 Å2 ChemAxon Rotatable Bond Count 1 ChemAxon Refractivity 30.45 m3·mol-1 ChemAxon Polarizability 11.13 Å3 ChemAxon Number of Rings 1 ChemAxon Bioavailability 1 ChemAxon Rule of Five Yes ChemAxon Ghose Filter No ChemAxon Veber's Rule No ChemAxon MDDR-like Rule No ChemAxon - Predicted ADMET features
Property Value Probability Human Intestinal Absorption + 0.9813 Blood Brain Barrier + 0.9745 Caco-2 permeable + 0.7222 P-glycoprotein substrate Non-substrate 0.8219 P-glycoprotein inhibitor I Non-inhibitor 0.9709 P-glycoprotein inhibitor II Non-inhibitor 0.9971 Renal organic cation transporter Non-inhibitor 0.8985 CYP450 2C9 substrate Non-substrate 0.8861 CYP450 2D6 substrate Non-substrate 0.876 CYP450 3A4 substrate Non-substrate 0.7754 CYP450 1A2 substrate Non-inhibitor 0.8791 CYP450 2C9 inhibitor Non-inhibitor 0.9545 CYP450 2D6 inhibitor Non-inhibitor 0.9731 CYP450 2C19 inhibitor Non-inhibitor 0.9547 CYP450 3A4 inhibitor Non-inhibitor 0.9697 CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.9353 Ames test Non AMES toxic 0.9133 Carcinogenicity Non-carcinogens 0.9321 Biodegradation Not ready biodegradable 0.9602 Rat acute toxicity 1.8145 LD50, mol/kg Not applicable hERG inhibition (predictor I) Weak inhibitor 0.9939 hERG inhibition (predictor II) Non-inhibitor 0.9617
Spectra
- Mass Spec (NIST)
- Download (8.68 KB)
- Spectra
Taxonomy
- Description
- This compound belongs to the class of organic compounds known as pyrazines. These are compounds containing a pyrazine ring, which is a six-member aromatic heterocycle, that consists of two nitrogen atoms (at positions 1 and 4) and four carbon atoms.
- Kingdom
- Organic compounds
- Super Class
- Organoheterocyclic compounds
- Class
- Diazines
- Sub Class
- Pyrazines
- Direct Parent
- Pyrazines
- Alternative Parents
- Heteroaromatic compounds / Carboximidic acids / Azacyclic compounds / Organopnictogen compounds / Organooxygen compounds / Organonitrogen compounds / Hydrocarbon derivatives
- Substituents
- Pyrazine / Heteroaromatic compound / Azacycle / Carboximidic acid derivative / Carboximidic acid / Organic nitrogen compound / Organic oxygen compound / Organopnictogen compound / Hydrocarbon derivative / Organooxygen compound
- Molecular Framework
- Aromatic heteromonocyclic compounds
- External Descriptors
- pyrazines, monocarboxylic acid amide (CHEBI:45285) / a carboxamide (PYRAZINAMIDE)
Targets
- Kind
- Protein
- Organism
- Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Not Available
- Specific Function
- Enoyl-[acyl-carrier-protein] reductase (nadh) activity
- Gene Name
- fas
- Uniprot ID
- P95029
- Uniprot Name
- Probable fatty acid synthase Fas (Fatty acid synthetase)
- Molecular Weight
- 326251.13 Da
References
- Zimhony O, Cox JS, Welch JT, Vilcheze C, Jacobs WR Jr: Pyrazinamide inhibits the eukaryotic-like fatty acid synthetase I (FASI) of Mycobacterium tuberculosis. Nat Med. 2000 Sep;6(9):1043-7. [PubMed:10973326]
- Ngo SC, Zimhony O, Chung WJ, Sayahi H, Jacobs WR Jr, Welch JT: Inhibition of isolated Mycobacterium tuberculosis fatty acid synthase I by pyrazinamide analogs. Antimicrob Agents Chemother. 2007 Jul;51(7):2430-5. Epub 2007 May 7. [PubMed:17485499]
- Zimhony O, Vilcheze C, Arai M, Welch JT, Jacobs WR Jr: Pyrazinoic acid and its n-propyl ester inhibit fatty acid synthase type I in replicating tubercle bacilli. Antimicrob Agents Chemother. 2007 Feb;51(2):752-4. Epub 2006 Nov 13. [PubMed:17101678]
- Schroeder EK, de Souza N, Santos DS, Blanchard JS, Basso LA: Drugs that inhibit mycolic acid biosynthesis in Mycobacterium tuberculosis. Curr Pharm Biotechnol. 2002 Sep;3(3):197-225. [PubMed:12164478]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Xanthine oxidase activity
- Specific Function
- Key enzyme in purine degradation. Catalyzes the oxidation of hypoxanthine to xanthine. Catalyzes the oxidation of xanthine to uric acid. Contributes to the generation of reactive oxygen species. Ha...
- Gene Name
- XDH
- Uniprot ID
- P47989
- Uniprot Name
- Xanthine dehydrogenase/oxidase
- Molecular Weight
- 146422.99 Da
References
- Moriwaki Y, Yamamoto T, Nasako Y, Takahashi S, Suda M, Hiroishi K, Hada T, Higashino K: In vitro oxidation of pyrazinamide and allopurinol by rat liver aldehyde oxidase. Biochem Pharmacol. 1993 Sep 14;46(6):975-81. [PubMed:8216357]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Xanthine dehydrogenase activity
- Specific Function
- Oxidase with broad substrate specificity, oxidizing aromatic azaheterocycles, such as N1-methylnicotinamide and N-methylphthalazinium, as well as aldehydes, such as benzaldehyde, retinal, pyridoxal...
- Gene Name
- AOX1
- Uniprot ID
- Q06278
- Uniprot Name
- Aldehyde oxidase
- Molecular Weight
- 147916.735 Da
References
- Moriwaki Y, Yamamoto T, Nasako Y, Takahashi S, Suda M, Hiroishi K, Hada T, Higashino K: In vitro oxidation of pyrazinamide and allopurinol by rat liver aldehyde oxidase. Biochem Pharmacol. 1993 Sep 14;46(6):975-81. [PubMed:8216357]
Drug created on June 13, 2005 07:24 / Updated on April 06, 2020 22:00
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