Identification

Name
Pyrazinamide
Accession Number
DB00339
Description

A pyrazine that is used therapeutically as an antitubercular agent.

Type
Small Molecule
Groups
Approved, Investigational
Structure
Thumb
Weight
Average: 123.1127
Monoisotopic: 123.043261797
Chemical Formula
C5H5N3O
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

Pharmacology

Indication

For the initial treatment of active tuberculosis in adults and children when combined with other antituberculous agents.

Associated Conditions
Contraindications & Blackbox Warnings
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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

TargetActionsOrganism
AFatty acid synthetase
inhibitor
Mycobacterium 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.

Hover over products below to view reaction partners

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
Adverse Effects
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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

Interactions

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.
DrugInteraction
AbacavirPyrazinamide may decrease the excretion rate of Abacavir which could result in a higher serum level.
AcarboseAcarbose may decrease the excretion rate of Pyrazinamide which could result in a higher serum level.
AceclofenacAceclofenac may decrease the excretion rate of Pyrazinamide which could result in a higher serum level.
AcemetacinAcemetacin may decrease the excretion rate of Pyrazinamide which could result in a higher serum level.
AcenocoumarolThe risk or severity of bleeding can be increased when Pyrazinamide is combined with Acenocoumarol.
AcetaminophenAcetaminophen may decrease the excretion rate of Pyrazinamide which could result in a higher serum level.
AcetazolamideAcetazolamide may increase the excretion rate of Pyrazinamide which could result in a lower serum level and potentially a reduction in efficacy.
Acetylsalicylic acidAcetylsalicylic acid may decrease the excretion rate of Pyrazinamide which could result in a higher serum level.
AclidiniumPyrazinamide may decrease the excretion rate of Aclidinium which could result in a higher serum level.
AcrivastinePyrazinamide may decrease the excretion rate of Acrivastine which could result in a higher serum level.
Additional Data Available
  • Extended Description
    Extended Description

    Extended description of the mechanism of action and particular properties of each drug interaction.

    Learn more
  • Severity
    Severity

    A severity rating for each drug interaction, from minor to major.

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  • Evidence Level
    Evidence Level

    A rating for the strength of the evidence supporting each drug interaction.

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  • Action
    Action

    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.

Products

International/Other Brands
Piraldina (Bracco) / Prazina (Armoxindo) / Pyrafat (Riemser) / Pyrazide (Sanofi-Aventis) / Tebrazid (Valeant) / Tisamid (Orion)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
TebrazidTabletOralValeant Canada Lp Valeant Canada S.E.C.1973-12-31Not applicableCanada
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

    Learn more
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Pdp-pyrazinamideTabletOralPendopharm Division Of Pharmascience Inc1984-12-31Not applicableCanada
PyrazinamideTablet500 mg/1OralRemedy Repack2013-02-262014-02-27Us
PyrazinamideTablet500 mg/1OralDepartment Of State Health Services, Pharmacy Branch1995-04-01Not applicableUs
PyrazinamideTablet500 mg/1OralMajor Pharmaceuticals1971-06-03Not applicableUs
PyrazinamideTablet500 mg/1OralClinical Solutions Wholsesale1971-06-032017-06-15Us
PyrazinamideTablet500 mg/1OralREMEDYREPACK INC.2008-05-212017-08-03Us
PyrazinamideTablet500 mg/1OralA-S Medication Solutions1971-06-032019-09-30Us
PyrazinamideTablet500 mg/1OralEffcon Laboratories, Inc.1992-06-301995-12-29Us
PyrazinamideTablet500 mg/1OralRemedy Repack2015-06-262016-06-26Us
PyrazinamideTablet500 mg/1OralA-S Medication Solutions1995-04-01Not applicableUs
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

    Learn more
  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

    Learn more
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
RifaterPyrazinamide (300 mg) + Isoniazid (50 mg) + Rifampicin (120 mg)TabletOralSanofi Aventis1995-12-312017-03-29Canada
RifaterPyrazinamide (300 mg/1) + Isoniazid (50 mg/1) + Rifampicin (120 mg/1)Tablet, sugar coatedOralsanofi-aventis U.S. LLC1994-05-31Not applicableUs
RifaterPyrazinamide (300 mg/1) + Isoniazid (50 mg/1) + Rifampicin (120 mg/1)Tablet, sugar coatedOralRemedy Repack2010-09-152010-09-16Us

Categories

ATC Codes
J04AK01 — PyrazinamideJ04AM06 — Rifampicin, pyrazinamide, ethambutol and isoniazidJ04AM05 — Rifampicin, pyrazinamide and isoniazid
Drug Categories
Chemical TaxonomyProvided by Classyfire
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
Aromatic heteromonocyclic compound / Azacycle / Carboximidic acid / Carboximidic acid derivative / Heteroaromatic compound / Hydrocarbon derivative / Organic nitrogen compound / Organic oxygen compound / Organonitrogen compound / Organooxygen compound
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
pyrazines, monocarboxylic acid amide (CHEBI:45285) / a carboxamide (PYRAZINAMIDE)

Chemical Identifiers

UNII
2KNI5N06TI
CAS number
98-96-4
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

References

General References
  1. 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]
  2. 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]
  3. 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]
  4. 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]
  5. 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]
  6. 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]
  7. 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]
  8. 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]
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
AHFS Codes
  • 08:16.04 — Antituberculosis Agents
PDB Entries
3r4x / 3r55 / 5fpd
MSDS
Download (73.6 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4Active Not RecruitingPreventionHuman Immunodeficiency Virus Type 1 (HIV-1) Infection1
4Active Not RecruitingTreatmentHuman Immunodeficiency Virus (HIV) Infections2
4CompletedPreventionHuman Immunodeficiency Virus (HIV) Infections1
4CompletedPreventionHuman Immunodeficiency Virus (HIV) Infections / Tuberculosis (TB)1
4CompletedTreatmentDrug Induced Hepatotoxicity / Tuberculosis (TB)1
4RecruitingTreatmentAIDS With Tuberculosis1
4RecruitingTreatmentPulmonary Tuberculosis (TB)1
4RecruitingTreatmentTuberculosis, Spinal1
4Unknown StatusTreatmentHepatitis / Pulmonary Tuberculosis (TB)1
4Unknown StatusTreatmentReinfection Pulmonary Tuberculosis1

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
FormRouteStrength
Tablet, film coatedOral500 MG
Tablet500 MG
TabletOral500 mg/1
TabletOral
Tablet, sugar coatedOral
TabletOral
Prices
Unit descriptionCostUnit
Rifater tablet3.1USD tablet
Pyrazinamide 500 mg tablet1.26USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)192 °CPhysProp
water solubility1.5E+004 mg/L (at 25 °C)MERCK INDEX (1996)
logP-0.60HANSCH,C ET AL. (1995)
logS-0.91ADME Research, USCD
pKa-0.5Not Available
Predicted Properties
PropertyValueSource
Water Solubility93.7 mg/mLALOGPS
logP-0.71ALOGPS
logP-1.2ChemAxon
logS-0.12ALOGPS
pKa (Strongest Acidic)13.06ChemAxon
pKa (Strongest Basic)-0.68ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area68.87 Å2ChemAxon
Rotatable Bond Count1ChemAxon
Refractivity30.45 m3·mol-1ChemAxon
Polarizability11.13 Å3ChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.9813
Blood Brain Barrier+0.9745
Caco-2 permeable+0.7222
P-glycoprotein substrateNon-substrate0.8219
P-glycoprotein inhibitor INon-inhibitor0.9709
P-glycoprotein inhibitor IINon-inhibitor0.9971
Renal organic cation transporterNon-inhibitor0.8985
CYP450 2C9 substrateNon-substrate0.8861
CYP450 2D6 substrateNon-substrate0.876
CYP450 3A4 substrateNon-substrate0.7754
CYP450 1A2 substrateNon-inhibitor0.8791
CYP450 2C9 inhibitorNon-inhibitor0.9545
CYP450 2D6 inhibitorNon-inhibitor0.9731
CYP450 2C19 inhibitorNon-inhibitor0.9547
CYP450 3A4 inhibitorNon-inhibitor0.9697
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9353
Ames testNon AMES toxic0.9133
CarcinogenicityNon-carcinogens0.9321
BiodegradationNot ready biodegradable0.9602
Rat acute toxicity1.8145 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9939
hERG inhibition (predictor II)Non-inhibitor0.9617
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Download (8.68 KB)
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available
LC-MS/MS Spectrum - LC-ESI-QQ , positiveLC-MS/MSsplash10-0ab9-1900000000-d29284f74cafc89d62ad
LC-MS/MS Spectrum - LC-ESI-QQ , positiveLC-MS/MSsplash10-001i-9200000000-f1f9853e24fa676ffa99
LC-MS/MS Spectrum - LC-ESI-QQ , positiveLC-MS/MSsplash10-001j-9000000000-7be5ab1fa895dc272521
LC-MS/MS Spectrum - LC-ESI-QQ , positiveLC-MS/MSsplash10-000t-9000000000-9c4235602fdfd2d2cdeb
LC-MS/MS Spectrum - LC-ESI-QQ , positiveLC-MS/MSsplash10-014i-3009000000-ab4d0160c375af6d52ee
1H NMR Spectrum1D NMRNot Applicable
13C NMR Spectrum1D NMRNot Applicable

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
  1. 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]
  2. 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]
  3. 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]
  4. 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
  1. 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
  1. 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 August 04, 2020 17:12

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