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	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.

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Pyrazinamide
- 5-hydroxypyrazinamide

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.

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.

Drug	Interaction
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Abacavir	Pyrazinamide may decrease the excretion rate of Abacavir 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.
Acetylsalicylic acid	Acetylsalicylic acid may decrease the excretion rate of Pyrazinamide which could result in a higher serum level.
Aclidinium	Pyrazinamide may decrease the excretion rate of Aclidinium which could result in a higher serum level.
Acrivastine	Pyrazinamide may decrease the excretion rate of Acrivastine which could result in a higher serum level.
Acyclovir	Acyclovir may decrease the excretion rate of Pyrazinamide which could result in a higher serum level.

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Food Interactions

Take with or without food. The absorption is unaffected by food.

Products

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International/Other Brands

Piraldina (Bracco) / Prazina (Armoxindo) / Pyrafat (Riemser) / Pyrazide (Sanofi-Aventis) / Tebrazid (Valeant) / Tisamid (Orion)

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Tebrazid	Tablet	500 mg	Oral	Bausch Health, Canada Inc.	1973-12-31	Not applicable

Generic Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
Pdp-pyrazinamide	Tablet	500 mg	Oral	Pendopharm Division Of Pharmascience Inc	1984-12-31	Not applicable
PMS-pyrazinamide	Tablet	500 mg	Oral	Pharmascience Inc	Not applicable	Not applicable
Pyrazinamide	Tablet	500 mg/1	Oral	Novitium Pharma Llc	2021-05-11	Not applicable
Pyrazinamide	Tablet	500 mg/1	Oral	Remedy Repack	2010-03-15	2014-01-08
Pyrazinamide	Tablet	500 mg/1	Oral	Clinical Solutions Wholsesale	1971-06-03	2017-06-15
Pyrazinamide	Tablet	500 mg/1	Oral	A-S Medication Solutions	1995-04-01	Not applicable
Pyrazinamide	Tablet	500 mg/1	Oral	Physicians Total Care, Inc.	1971-06-03	2003-06-30
Pyrazinamide	Tablet	500 mg/1	Oral	REMEDYREPACK INC.	2023-02-26	Not applicable
Pyrazinamide	Tablet	500 mg/1	Oral	Department Of State Health Services, Pharmacy Branch	1995-04-01	Not applicable
Pyrazinamide	Tablet	500 mg/1	Oral	American Health Packaging	2016-10-24	2021-09-30

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
Rifater	Pyrazinamide (300 mg) + Isoniazid (50 mg) + Rifampicin (120 mg)	Tablet	Oral	Sanofi Aventis	1995-12-31	2017-03-29
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
RIFATER	Pyrazinamide (250 MG) + Isoniazid (80 MG) + Rifampicin (120 MG)	Tablet, sugar coated	Oral	บริษัท ซาโนฟี่-อเวนตีส (ประเทศไทย) จำกัด	2000-07-09	Not applicable
RIP-PED	Pyrazinamide (150 MG) + Isoniazid (30 MG) + Rifampicin (60 MG)	Tablet, coated	Oral	บริษัท ที.พี.ดรัก แลบบอราทอรี่ส์ (1969) จำกัด	2019-12-19	Not applicable
TPUTE-RIPE	Pyrazinamide (400 MG) + Isoniazid (75 MG) + Rifampicin (150 MG)	Tablet, film coated	Oral	บริษัท ที.พี.ดรัก แลบบอราทอรี่ส์ (1969) จำกัด	2018-11-01	Not applicable
ฟอร์ค๊อส - แทรค	Pyrazinamide (400 MG) + Ethambutol hydrochloride (275 MG) + Isoniazid (75 MG) + Rifampicin (150 MG)	Tablet, coated	Oral	บริษัท แอตแลนต้า เมดดิคแคร์ จำกัด จำกัด	2019-10-10	Not applicable
ริมสตาร์ 4 - FDC	Pyrazinamide (75 MG) + Ethambutol hydrochloride (275 MG) + Isoniazid (400 MG) + Rifampicin (150 MG)	Tablet, film coated	Oral	องค์การเภสัชกรรม	2008-05-19	Not applicable
ไรป์ - 900	Pyrazinamide (400 mg) + Ethambutol hydrochloride (275 mg) + Isoniazid (75 mg) + Rifampicin (150 mg)	Tablet, coated	Oral	บริษัท ยูเมด้า จำกัด	2010-01-18	2020-08-23
ไรฟาเทอ	Pyrazinamide (250 MG) + Isoniazid (80 MG) + Rifampicin (120 MG)	Tablet, sugar coated	Oral	บริษัท โอลิค (ประเทศไทย) จำกัด	1991-11-05	Not applicable

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

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. [Article]
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. [Article]
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. [Article]
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. [Article]
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. [Article]
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. [Article]
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. [Article]
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. [Article]

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

PDB Entries

3r4x / 3r55 / 5fpd / 5rtm / 8h0o

MSDS

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Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
4	Active Not Recruiting	Treatment	Multidrug Resistant Tuberculosis	1
4	Completed	Prevention	Human Immunodeficiency Virus (HIV) Infections	1
4	Completed	Prevention	Human Immunodeficiency Virus (HIV) Infections / Tuberculosis (TB)	1
4	Completed	Prevention	Human Immunodeficiency Virus Type 1 (HIV-1) Infection	1
4	Completed	Treatment	Drug Induced Hepatotoxicity / Tuberculosis (TB)	1
4	Completed	Treatment	Human Immunodeficiency Virus (HIV) Infections	1
4	Recruiting	Treatment	Multidrug Resistant Tuberculosis	1
4	Unknown Status	Treatment	AIDS With Tuberculosis	1
4	Unknown Status	Treatment	Hepatitis / Pulmonary Tuberculosis (TB)	1
4	Unknown Status	Treatment	Pulmonary Tuberculosis (TB)	1

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
Tablet	Oral	500 mg/1
Tablet, film coated	Oral
Tablet, soluble	Oral
Tablet, sugar coated	Oral
Tablet, chewable	Buccal
Tablet, chewable	Oral
Tablet, film coated	Oral	500 MG
Tablet, coated	Oral
Tablet	Oral	500 mg

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)	-0.55	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

ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)

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Spectra

Spectrum	Spectrum Type	Splash Key
Predicted GC-MS Spectrum - GC-MS	Predicted GC-MS	Not Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
LC-MS/MS Spectrum - LC-ESI-QQ , positive	LC-MS/MS	splash10-0ab9-1900000000-d29284f74cafc89d62ad
LC-MS/MS Spectrum - LC-ESI-QQ , positive	LC-MS/MS	splash10-001i-9200000000-f1f9853e24fa676ffa99
LC-MS/MS Spectrum - LC-ESI-QQ , positive	LC-MS/MS	splash10-001j-9000000000-7be5ab1fa895dc272521
LC-MS/MS Spectrum - LC-ESI-QQ , positive	LC-MS/MS	splash10-000t-9000000000-9c4235602fdfd2d2cdeb
LC-MS/MS Spectrum - LC-ESI-QQ , positive	LC-MS/MS	splash10-014i-3009000000-ab4d0160c375af6d52ee
1H NMR Spectrum	1D NMR	Not Applicable
13C NMR Spectrum	1D NMR	Not Applicable

Targets

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Details1. Fatty acid synthetase

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. [Article]
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. [Article]
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. [Article]
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. [Article]

Enzymes

Details1. Aldehyde oxidase

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. [Article]

Details2. Xanthine dehydrogenase/oxidase

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. [Article]

Drug created at June 13, 2005 13:24 / Updated at November 28, 2023 22:14

Pyrazinamide

Identification

Structure for Pyrazinamide (DB00339)

Pharmacology

Interactions

Products

Categories

Chemical Identifiers

References

Clinical Trials

Pharmacoeconomics

Properties

Spectra

Targets

References

Enzymes

References

References