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Identification
Name Pyrazinamide
Accession Number DB00339 (APRD01206)
Type small molecule
Groups approved
Description

A pyrazine that is used therapeutically as an antitubercular agent.
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
  • Pirazimida
  • Pirazinamid
  • Pyrazinamdie
  • Pyrazine carboxylamide
  • Pyrazineamide
  • Pyrazinecarboxamide
  • Pyrazinecarboxylic acid amide
  • Pyrazinoic acid amide
  • PZA
Brand names
  • Aldinamid
  • Aldinamide
  • Braccopiral
  • Corsazinmid
  • Dipimide
  • Eprazin
  • Farmizina
  • Isopas
  • Lynamide
  • Novamid
  • Pezetamid
  • Piraldina
  • Pirilene
  • pms-Pyrazinamide
  • Prazina
  • Pyrafat
  • Pyramide
  • Pyrazide
  • Pyrazinamide BP 2000
  • Rifater
  • Rozide
  • Tebrazid
  • Tebrazio
  • Unipyranamide
  • Zinamide
  • Zinastat
Brand name mixtures
  • Rifater - Tab (Isoniazid + Pyrazinamide + Rifampin)
Categories
  • Antitubercular Agents
CAS number 98-96-4
Weight Average: 123.1127
Monoisotopic: 123.043261797
Chemical Formula C5H5N3O
InChI Key InChIKey=IPEHBUMCGVEMRF-UHFFFAOYSA-N
InChI
InChI=1S/C5H5N3O/c6-5(9)4-3-7-1-2-8-4/h1-3H,(H2,6,9)
Plain Text
IUPAC Name
pyrazine-2-carboxamide
SMILES
NC(=O)C1=NC=CN=C1
Plain Text
Mass Spec show (8.7 KB)
Taxonomy
Kingdom Organic
Classes
  • Pyrazines
Substructures
  • Amino Ketones
  • Carbamates and Derivatives
  • Pyrazines
  • Heterocyclic compounds
  • Aromatic compounds
  • Carboxamides and Derivatives
  • Imines
  • Carboxylic Acids and Derivatives
Pharmacology
Indication For the initial treatment of active tuberculosis in adults and children when combined with other antituberculous agents.
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 is an important sterilizing prodrug that shortens tuberculosis (TB) therapy. However, the mechanism of action of pyrazinamide is poorly understood because of its unusual properties. In literature it has been written that the pyrazinoic acid (POA), the active moiety of pyrazinamide, disrupted membrane energetics and inhibited membrane transport function at acid pH in Mycobacterium tuberculosis. The antimycobacterial activity appears to partly depend on conversion of the drug to POA. Susceptible strains of M. tuberculosis produce pyrazinamidase, an enzyme that deaminates pyrazinamide to POA, and the vitro susceptibility of a given strain of the organism appears to correspond to its pyrazinamidase activity. Experimental evidence suggests that pyrazinamide diffuses into M. tuberculosis in a passive manner, is converted into POA by pyrazinamidase, and because of an inefficient efflux system, accumulates in huge amounts in the bacterial cytoplasm. The accumulation of POA lowers the intracellular pH to a suboptimal level that is likely to inactivate a vital target enzyme such as fatty acid synthase. Recent studies (2007) demonstrated that pyrazinamide and its analogs inhibit the activity of purified FAS I.
Absorption Rapidly and well absorbed from the gastrointestinal tract.
Volume of distribution Not Available
Protein binding ~10% (bound to plasma proteins)
Metabolism

Hepatic.

Enzyme Metabolite Reaction Km Vmax
Xanthine dehydrogenase/oxidase oxidation
Aldehyde oxidase 5-hydroxypyrazinamide oxidation
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
Pharmacoeconomics
Manufacturers
  • Dava pharmaceuticals inc
  • Mikart inc
Packagers
Dosage forms
Form Route Strength
Tablet Oral
Prices
Unit description Cost Unit
Rifater tablet 3.1 USD tablet
Pyrazinamide 500 mg tablet 1.26 USD tablet
Patents Not Available
Properties
State solid
Melting point 192 oC
Experimental Properties
Property Value Source
water solubility 1.5E+004 mg/L PhysProp
logP -1 PhysProp
logS -0.91 [ADME Research, USCD] PhysProp
pKa -0.5 Various sources
Predicted Properties
Property Value Source
water solubility 9.37e+01 g/l ALOGPS
logP -0.71 ALOGPS
logP -1.23 ChemAxon Molconvert
logS -0.12 ALOGPS
pKa ChemAxon Molconvert
hydrogen acceptor count 3 ChemAxon Molconvert
hydrogen donor count 1 ChemAxon Molconvert
polar surface area 68.87 ChemAxon Molconvert
rotatable bond count 1 ChemAxon Molconvert
refractivity 30.45 ChemAxon Molconvert
polarizability 11.13 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference
  1. 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
  2. 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
  3. 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
  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
External Links
Resource Link
KEGG Drug D00144 Link_out
KEGG Compound C01956 Link_out
PubChem Compound 1046 Link_out
PubChem Substance 46507478 Link_out
ChemSpider 1017 Link_out
ChEBI 8656 Link_out
ChEMBL 8656 Link_out
Therapeutic Targets Database DAP000660 Link_out
PharmGKB PA451182 Link_out
Drug Product Database 618810 Link_out
RxList http://www.rxlist.com/pyrazinamide-drug.htm Link_out
Drugs.com http://www.drugs.com/cdi/pyrazinamide.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Pyrazinamide Link_out
ATC Codes
  • J04AK01
AHFS Codes
  • 08:16.04
PDB Entries Not Available
FDA label Not Available
MSDS show (73.6 KB)
Interactions
Drug Interactions Not Available
Food Interactions
  • Take without regard to meals.
Targets

1. PROBABLE FATTY ACID SYNTHASE FAS (FATTY ACID SYNTHETASE)

Pharmacological action: yes
Actions: inhibitor
Organism class: bacterial
UniProt ID: P95029 Link_out
Gene: fas Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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
  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
  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
  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
Enzymes

1. Xanthine dehydrogenase/oxidase

Actions: substrate

This enzyme can be converted from the dehydrogenase form (D) to the oxidase form (O) irreversibly by proteolysis or reversibly through the oxidation of sulfhydryl groups

UniProt ID: P47989 Link_out
Gene: XDH Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

2. Aldehyde oxidase

Actions: substrate

An aldehyde + H(2)O + O(2) = a carboxylic acid + H(2)O(2)

UniProt ID: Q06278 Link_out
Gene: AOX1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

3. Cytochrome P450 1A2

Actions: substrate

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 N3-demethylation. Also acts in the metabolism of aflatoxin B1 and acetaminophen

UniProt ID: P05177 Link_out
Gene: CYP1A2
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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. Epub 2009 Nov 24. Pubmed

4. Cytochrome P450 3A4

Actions: substrate

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 xenobiotics. The enzyme also hydroxylates etoposide

UniProt ID: P08684 Link_out
Gene: CYP3A4
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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. Epub 2009 Nov 24. Pubmed
Comments
Drug created on June 13, 2005 07:24 / Updated on November 10, 2010 13:38

This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.