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Identification
NamePyrazinamide
Accession NumberDB00339  (APRD01206)
TypeSmall Molecule
GroupsApproved
Description

A pyrazine that is used therapeutically as an antitubercular agent.

Structure
Thumb
Synonyms
2-carbamylpyrazine
2-pyrazinecarboxamide
Aldinamide
Pirazinamida
Pirazinamide
Pyrazinamid
Pyrazinamida
Pyrazinamide
Pyrazinamidum
Pyrazine carboxamide
pyrazine-2-carboxamide
Pyrazineamide
Pyrazinecarboxamide
Pyrazinoic acid amide
Pyrizinamide
External Identifiers
  • PZA
  • Z
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Pdp-pyrazinamidetablet500 mgoralPendopharm Division Of De Pharmascience Inc1984-12-31Not applicableCanada
Tebrazid Tab 500mgtablet500 mgoralValeant Canada Lp Valeant Canada S.E.C.1973-12-31Not applicableCanada
Approved Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Pyrazinamidetablet500 mg/1oralREMEDYREPACK INC.2013-08-21Not applicableUs
Pyrazinamidetablet500 mg/1oralVersa Pharm Incorporated1995-04-01Not applicableUs
Pyrazinamidetablet500 mg/1oralAmerican Health Packaging2015-09-01Not applicableUs
Pyrazinamidetablet500 mg/1oralClinical Solutions Wholesale, Llc1971-06-03Not applicableUs
Pyrazinamidetablet500 mg/1oralREMEDYREPACK INC.2013-02-26Not applicableUs
Pyrazinamidetablet500 mg/1oralA S Medication Solutions1995-04-01Not applicableUs
Pyrazinamidetablet500 mg/1oralREMEDYREPACK INC.2011-06-30Not applicableUs
Pyrazinamidetablet500 mg/1oralDepartment Of State Health Services, Pharmacy Branch1995-04-01Not applicableUs
Pyrazinamidetablet500 mg/1oralMikart, Inc.1992-06-30Not applicableUs
Pyrazinamidetablet500 mg/1oralDAVA Pharmaceuticals, Inc.1971-06-03Not applicableUs
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International Brands
NameCompany
PiraldinaBracco
PrazinaArmoxindo
PyrafatRiemser
PyrazideSanofi-Aventis
TebrazidValeant
TisamidOrion
Brand mixtures
NameLabellerIngredients
RifaterSanofi Aventis U.S. Llc
SaltsNot Available
Categories
UNII2KNI5N06TI
CAS number98-96-4
WeightAverage: 123.1127
Monoisotopic: 123.043261797
Chemical FormulaC5H5N3O
InChI KeyInChIKey=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
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as pyrazinecarboxamides. These are compounds containing a pyrazine ring which bears a carboxamide.
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassDiazines
Sub ClassPyrazines
Direct ParentPyrazinecarboxamides
Alternative Parents
Substituents
  • Pyrazinecarboxamide
  • Heteroaromatic compound
  • Primary carboxylic acid amide
  • Carboxamide group
  • Azacycle
  • Carboxylic acid derivative
  • Hydrocarbon derivative
  • Organooxygen compound
  • Organonitrogen compound
  • Carbonyl group
  • Aromatic heteromonocyclic compound
Molecular FrameworkAromatic heteromonocyclic compounds
External Descriptors
Pharmacology
IndicationFor the initial treatment of active tuberculosis in adults and children when combined with other antituberculous agents.
PharmacodynamicsPyrazinamide 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 actionPyrazinamide diffuses into M. tuberculosis, where the enzyme pyrazinamidase converts pyrazinamide to the active form pyrazinoic acid. Under acidic conditions, the pyrazinoic acid that slowly leaks out converts to the protonated conjugate acid, which is thought to diffuse easily back into the bacilli and accumulate. 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 (PMID: 11914348). 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 (PMID: 17101678). 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 (PMID: 17485499). 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 (PMID: 21835980).
Related Articles
AbsorptionRapidly and well absorbed from the gastrointestinal tract.
Volume of distributionNot Available
Protein binding~10% (bound to plasma proteins)
Metabolism

Hepatic.

SubstrateEnzymesProduct
Pyrazinamide
5-hydroxypyrazinamideDetails
Route of eliminationApproximately 70% of an oral dose is excreted in the urine, mainly by glomerular filtration within 24 hours
Half life9-10 hours (normal conditions)
ClearanceNot Available
ToxicitySide 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
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
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 )
Pharmacoeconomics
Manufacturers
  • Dava pharmaceuticals inc
  • Mikart inc
Packagers
Dosage forms
FormRouteStrength
Tabletoral500 mg/1
Tabletoral
Tablet, sugar coatedoral
Tabletoral500 mg
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.
PatentsNot Available
Properties
StateSolid
Experimental Properties
PropertyValueSource
melting point192 °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 FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Download (8.68 KB)
Spectra
Spectrum TypeDescriptionSplash Key
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, NegativeNot Available
References
Synthesis ReferenceNot Available
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 ]
External Links
ATC CodesJ04AM06J04AK01J04AM05
AHFS Codes
  • 08:16.04
PDB EntriesNot Available
FDA labelNot Available
MSDSDownload (73.6 KB)
Interactions
Drug Interactions
Drug
CyclosporineThe serum concentration of Cyclosporine can be increased when it is combined with Pyrazinamide.
RifampicinPyrazinamide may increase the hepatotoxic activities of Rifampicin.
Food Interactions
  • Take without regard to meals.

Targets

1. Fatty acid synthetase I (FASI)
Kind
Protein
Organism
Mycobacterium tuberculosis
Pharmacological action
yes
Actions
inhibitor
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
Human
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. Has also low oxidase activity towards aldehydes (in vitro).
Gene Name:
XDH
Uniprot ID:
P47989
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
Human
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, and vanillin. Plays a key role in the metabolism of xenobiotics and drugs containing aromatic azaheterocyclic substituents. Participates in the bioactivation of prodrugs such as famciclovir, catalyz...
Gene Name:
AOX1
Uniprot ID:
Q06278
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 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
Specific Function:
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. Most active in catalyzing 2-hydroxylation. Caffeine is metabolized primarily by cytochrome CYP1A2 in the liver through an initial N...
Gene Name:
CYP1A2
Uniprot ID:
P05177
Molecular Weight:
58293.76 Da
References
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Vitamin d3 25-hydroxylase activity
Specific Function:
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4-hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiot...
Gene Name:
CYP3A4
Uniprot ID:
P08684
Molecular Weight:
57342.67 Da
References
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256 ]
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Drug created on June 13, 2005 07:24 / Updated on August 17, 2016 12:23