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Identification
Name Ribavirin
Accession Number DB00811 (APRD00081)
Type small molecule
Groups approved
Description

A nucleoside antimetabolite antiviral agent that blocks nucleic acid synthesis and is used against both RNA and DNA viruses. [PubChem]
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
  • RBV
  • Ribavirin Triphosphate
  • Ribavirina [INN-Spanish]
  • Ribavirine [INN-French]
  • Ribavirinum [INN-Latin]
Brand names
  • Copegus
  • Rebetol
  • Rebetron
  • Rebretron
  • Ribamide
  • Ribamidil
  • Ribamidyl
  • Ribasphere
  • RIBAV
  • Ribavirin Capsules
  • Ribavirin-TP
  • RTC
  • RTCA
  • RTP
  • Tribavirin
  • Varazid
  • Vilona
  • Viramid
  • Virazid
  • Virazole
  • Virazole 5'-triphosphate
Brand name mixtures
  • Rebetron (Schering-Plough) (Ribavirin + Interferon alpha)
Categories
  • Antiviral Agents
  • Antimetabolites
CAS number 36791-04-5
Weight Average: 244.2047
Monoisotopic: 244.080769514
Chemical Formula C8H12N4O5
InChI Key InChIKey=IWUCXVSUMQZMFG-AFCXAGJDSA-N
InChI
InChI=1S/C8H12N4O5/c9-6(16)7-10-2-12(11-7)8-5(15)4(14)3(1-13)17-8/h2-5,8,13-15H,1H2,(H2,9,16)/t3-,4-,5-,8-/m1/s1
Plain Text
IUPAC Name
1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-1H-1,2,4-triazole-3-carboxamide
SMILES
NC(=O)C1=NN(C=N1)[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Carbohydrates
Substructures
  • Glycerol and Derivatives
  • Hydroxy Compounds
  • Amino Ketones
  • Triazoles
  • Ethers
  • Carbamates and Derivatives
  • Alcohols and Polyols
  • Heterocyclic compounds
  • Aromatic compounds
  • Carboxamides and Derivatives
  • Furans
  • Imines
  • Carboxylic Acids and Derivatives
  • Cyanamides
  • Carbohydrates
Pharmacology
Indication For the treatment of chronic hepatitis C and for respiratory syncytial virus (RSV).
Pharmacodynamics Ribavirin is an anti-viral drug active against a number of DNA and RNA viruses. It is a member of the nucleoside antimetabolite drugs that interfere with duplication of the viral genetic material. The drug inhibits the activity of the enzyme RNA dependent RNA polymerase, due to it's resemblence to building blocks of the RNA molecules. The oral form is used in the treatment of hepatitis C, in combination with interferon drugs. The aerosol form is used to treat respiratory syncytial virus-related diseases in children. The primary serious adverse effect of ribavirin is hemolytic anemia, which may worsen preexisting cardiac disease.
Mechanism of action Ribavirin is readily phosphorylated intracellularly by adenosine kinase to ribavirin mono-, di-, and triphosphate metabolites. Ribavirin triphosphate (RTP) is a potent competitive inhibitor of inosine monophosphate (IMP) dehydrogenase, viral RNA polymerase and messenger RNA (mRNA) guanylyltransferase (viral) and can be incorporated into RNA in RNA viral species.. Guanylyltranserase inhibition stops the capping of mRNA. These diverse effects result in a marked reduction of intracellular guanosine triphosphate (GTP) pools and inhibition of viral RNA and protein synthesis. Ribavirin is also incorporated into the viral genome causing lethal mutagenesis and a subsequent decrease in specific viral infectivity.
Absorption Rapidly and extensively absorbed following oral administration. However, due to first-pass metabolism, the absolute bioavailability averages 64%.
Volume of distribution Not Available
Protein binding Not Available
Metabolism

Hepatic. Results of in vitro studies using both human and rat liver microsome preparations indicated little or no cytochrome P450 enzyme-mediated metabolism of ribavirin, with minimal potential for P450 enzyme-based drug interactions. Ribavirin has two pathways of metabolism: (1) a reversible phosphorylation pathway in nucleated cells; and (2) a degradative pathway involving deribosylation and amide hydrolysis to yield a triazole carboxylic acid metabolite.

Enzyme Metabolite Reaction Km Vmax
Adenosine kinase Phosphorylation
Route of elimination Not Available
Half life 9.5 hours
Clearance
  • Apparent cl=26 L/h [A single oral dose]
Toxicity Side effects include "flu-like" symptoms, such as headache, fatigue, myalgia, and fever. The LD50 in mice is 2 g/kg orally and is associated with hypoactivity and gastrointestinal symptoms (estimated human equivalent dose of 0.17 g/kg, based on body surface area conversion).
Affected organisms
  • Hepatitis C virus, RSV and other RNA/DNA viruses
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Schering plough research institute
  • Three rivers pharmaceuticals llc
  • Aurobindo pharma ltd
  • Sandoz inc
  • Teva pharmaceuticals usa inc
  • Zydus pharmaceuticals usa inc
  • Valeant pharmaceuticals international
  • Schering corp
  • Hoffmann la roche inc
Packagers
Dosage forms
Form Route Strength
Aerosol Respiratory (inhalation)
Prices
Unit description Cost Unit
Virazole 6 gm vial 4512.21 USD vial
Ribatab 600 mg tablet 32.01 USD tablet
Ribasphere 600 mg tablet 24.88 USD tablet
Ribavirin 600 mg tablet 24.88 USD tablet
Ribatab 400 mg tablet 21.34 USD tablet
Ribavirin 500 mg tablet 20.74 USD tablet
Ribasphere 400 mg tablet 16.59 USD tablet
Ribavirin 400 mg tablet 16.59 USD tablet
Copegus 200 mg tablet 15.19 USD tablet
Rebetol 200 mg capsule 10.81 USD capsule
Ribasphere 200 mg capsule 10.33 USD capsule
Ribavirin 200 mg capsule 10.33 USD capsule
Ribasphere 200 mg tablet 8.29 USD tablet
Ribavirin 200 mg tablet 8.29 USD tablet
Ribavirin powder 3.21 USD g
Rebetol 40 mg/ml Solution 2.42 USD ml
Patents
Country Patent Number Approved Expires
United States 6790837 2003-10-05 2023-10-05
United States 6177074 1996-11-01 2016-11-01
Canada 2365412 2002-09-17 2018-12-21
Canada 2287056 2000-08-15 2018-12-21
Properties
State solid
Melting point 174-176 oC
Experimental Properties
Property Value Source
water solubility 142 mg/mL (max, at 25°C) PhysProp
logP -2.6 PhysProp
Predicted Properties
Property Value Source
water solubility 3.32e+01 g/l ALOGPS
logP -1.92 ALOGPS
logP -2.77 ChemAxon Molconvert
logS -0.87 ALOGPS
pKa 12.56 ChemAxon Molconvert
hydrogen acceptor count 7 ChemAxon Molconvert
hydrogen donor count 4 ChemAxon Molconvert
polar surface area 143.72 ChemAxon Molconvert
rotatable bond count 3 ChemAxon Molconvert
refractivity 64.57 ChemAxon Molconvert
polarizability 22.18 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference
  1. Sidwell RW, Bailey KW, Wong MH, Barnard DL, Smee DF: In vitro and in vivo influenza virus-inhibitory effects of viramidine. Antiviral Res. 2005 Oct;68(1):10-7. Pubmed
  2. Sidwell RW, Huffman JH, Khare GP, Allen LB, Witkowski JT, Robins RK: Broad-spectrum antiviral activity of Virazole: 1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide. Science. 1972 Aug 25;177(50):705-6. Pubmed
  3. Alvarez D, Dieterich DT, Brau N, Moorehead L, Ball L, Sulkowski MS: Zidovudine use but not weight-based ribavirin dosing impacts anaemia during HCV treatment in HIV-infected persons. J Viral Hepat. 2006 Oct;13(10):683-9. Pubmed
  4. Bani-Sadr F, Carrat F, Pol S, Hor R, Rosenthal E, Goujard C, Morand P, Lunel-Fabiani F, Salmon-Ceron D, Piroth L, Pialoux G, Bentata M, Cacoub P, Perronne C: Risk factors for symptomatic mitochondrial toxicity in HIV/hepatitis C virus-coinfected patients during interferon plus ribavirin-based therapy. J Acquir Immune Defic Syndr. 2005 Sep 1;40(1):47-52. Pubmed
External Links
Resource Link
KEGG Drug D00423 Link_out
PubChem Compound 37542 Link_out
PubChem Substance 46505883 Link_out
ChemSpider 34439 Link_out
Therapeutic Targets Database DNC001210 Link_out
PharmGKB PA451241 Link_out
HET RTP Link_out
Drug Product Database 0 Link_out
RxList www.rxlist.com/cgi/generic2/ribavirin.htm Link_out
Drugs.com http://www.drugs.com/cdi/ribavirin.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Ribavirin Link_out
ATC Codes
  • J05AB04
AHFS Codes
  • 08:18.32
PDB Entries
FDA label show (2.2 MB)
MSDS show (39.3 KB)
Interactions
Drug Interactions Not Available
Food Interactions Not Available
Targets

1. Inosine-5'-monophosphate dehydrogenase 1

Pharmacological action: yes
Actions: inhibitor

Rate limiting enzyme in the de novo synthesis of guanine nucleotides and therefore is involved in the regulation of cell growth. It may also have a role in the development of malignancy and the growth progression of some tumors

Organism class: human
UniProt ID: P20839 Link_out
Gene: IMPDH1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  2. Gish RG: Treating HCV with ribavirin analogues and ribavirin-like molecules. J Antimicrob Chemother. 2006 Jan;57(1):8-13. Epub 2005 Nov 17. Pubmed
  3. McHutchison JG, Shiffman ML, Cheung RC, Gordon SC, Wright TL, Pottage JC Jr, McNair L, Ette E, Moseley S, Alam J: A randomized, double-blind, placebo-controlled dose-escalation trial of merimepodib (VX-497) and interferon-alpha in previously untreated patients with chronic hepatitis C. Antivir Ther. 2005;10(5):635-43. Pubmed
  4. Leyssen P, De Clercq E, Neyts J: The anti-yellow fever virus activity of ribavirin is independent of error-prone replication. Mol Pharmacol. 2006 Apr;69(4):1461-7. Epub 2006 Jan 18. Pubmed

2. Adenosine kinase

Pharmacological action: yes
Actions: activator

ATP dependent phosphorylation of adenosine and other related nucleoside analogs to monophosphate derivatives. Serves as a potential regulator of concentrations of extracellular adenosine and intracellular adenine nucleotides

Organism class: human
UniProt ID: P55263 Link_out
Gene: ADK Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Wu JZ, Larson G, Walker H, Shim JH, Hong Z: Phosphorylation of ribavirin and viramidine by adenosine kinase and cytosolic 5’-nucleotidase II: Implications for ribavirin metabolism in erythrocytes. Antimicrob Agents Chemother. 2005 Jun;49(6):2164-71. Pubmed
  2. Kumarapperuma SC, Sun Y, Jeselnik M, Chung K, Parker WB, Jonsson CB, Arterburn JB: Structural effects on the phosphorylation of 3-substituted 1-beta-D-ribofuranosyl-1,2,4-triazoles by human adenosine kinase. Bioorg Med Chem Lett. 2007 Jun 1;17(11):3203-7. Epub 2007 Mar 12. Pubmed

3. Large structural protein

Pharmacological action: yes
Actions: antagonist

Displays RNA-directed RNA polymerase, mRNA guanylyl transferase, mRNA (guanine-7-N-)-methyltransferase and poly(A) synthetase activities. The viral mRNA guanylyl transferase displays a different biochemical reaction than the cellular enzyme. The template is composed of the viral RNA tightly encapsidated by the nucleoprotein (N). Functions either as transcriptase or as replicase. The transcriptase synthesizes subsequently the subgenomic RNAs, assuring their capping and polyadenylation by a stuttering mechanism. The transcriptase stutters on a specific sequence, resulting on a cotranscriptional editing of the phosphoprotein (P) mRNA. The replicase mode is dependent on intracellular N protein concentration. In this mode, the polymerase replicates the whole viral genome without recognizing the transcriptional signals

Organism class: viral
UniProt ID: P26676 Link_out
Gene: L
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed

4. RNA-directed RNA polymerase catalytic subunit

Pharmacological action: unknown
Actions: inhibitor

RNA-dependent RNA polymerase which is responsible for replication and transcription of virus segments. Binds the promoter sequence of the encapsidated viral RNA. Displays an endonuclease activity involved in cap-stealing. Cleaves cellular pre-mRNA to generate primers for viral transcription

Organism class: viral
UniProt ID: P16502 Link_out
Gene: PB1
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed
  3. Bougie I, Bisaillon M: Initial binding of the broad spectrum antiviral nucleoside ribavirin to the hepatitis C virus RNA polymerase. J Biol Chem. 2003 Dec 26;278(52):52471-8. Epub 2003 Oct 16. Pubmed

5. DNA

Pharmacological action: unknown
Actions: incorporation into and destabilization

DNA is the molecule of heredity, as it is responsible for the genetic propagation of most inherited traits. It is a polynucleic acid that carries genetic information on cell growth, division, and function. DNA consists of two long strands of nucleotides twisted into a double helix and held together by hydrogen bonds. The sequence of nucleotides determines hereditary characteristics. Each strand serves as the template for subsequent DNA replication and as a template for mRNA production, leading to protein synthesis via ribosomes.

Gene Sequence: FASTA

References:
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed
  3. Ren FY, Jin H, Piao XX, Piao FS: Ribavirin and IFN-alpha combination therapy induces CD4+ T-cell proliferation and Th1 cytokine secretion in patients with chronic hepatitis B. World J Gastroenterol. 2007 Nov 7;13(41):5440-5. Pubmed
  4. Crotty S, Cameron C, Andino R: Ribavirin’s antiviral mechanism of action: lethal mutagenesis? J Mol Med. 2002 Feb;80(2):86-95. Epub 2001 Dec 4. Pubmed

6. Cytosolic purine 5'-nucleotidase

Pharmacological action: unknown
Actions: inducer

May have a critical role in the maintenance of a constant composition of intracellular purine/pyrimidine nucleotides in cooperation with other nucleotidases. Preferentially hydrolyzes inosine 5-prime-monophosphate (IMP) and other purine nucleotides

Organism class: human
UniProt ID: P49902 Link_out
Gene: NT5C2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed

7. Ectonucleotide pyrophosphatase/phosphodiesterase family member 1

Pharmacological action: unknown
Actions: inhibitor

Has a broad specificity and cleaves a variety of substrates, including phosphodiester bonds of nucleotides and nucleotide sugars and pyrophosphate bonds of nucleotides and nucleotide sugars. Can hydrolyze nucleoside 5' triphosphates such as ATP, GTP, CTP, TTP and UTP to their corresponding monophosphates with release of pyrophosphate. Can hydrolyze diadenosine polyphosphates and 3',5'-cAMP to AMP. It may play a role in the regulation of pyrophosphate production, the regulation of the availability of nucleotide sugars in the endoplasmic reticulum and Golgi, and the regulation of purinergic signaling

Organism class: human
UniProt ID: P22413 Link_out
Gene: ENPP1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed
Enzymes

1. Adenosine kinase

Actions: substrate

ATP dependent phosphorylation of adenosine and other related nucleoside analogs to monophosphate derivatives. Serves as a potential regulator of concentrations of extracellular adenosine and intracellular adenine nucleotides

UniProt ID: P55263 Link_out
Gene: ADK Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Wu JZ, Larson G, Walker H, Shim JH, Hong Z: Phosphorylation of ribavirin and viramidine by adenosine kinase and cytosolic 5’-nucleotidase II: Implications for ribavirin metabolism in erythrocytes. Antimicrob Agents Chemother. 2005 Jun;49(6):2164-71. Pubmed
Transporters

1. Equilibrative nucleoside transporter 1

Actions: substrate

Mediates both influx and efflux of nucleosides across the membrane (equilibrative transporter). It is sensitive (ES) to low concentrations of the inhibitor nitrobenzylmercaptopurine riboside (NBMPR) and is sodium-independent. It has a higher affinity for adenosine. Inhibited by dipyridamole and dilazep (anticancer chemotherapeutics drugs)

UniProt ID: Q99808 Link_out
Gene: SLC29A1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Yamamoto T, Sugawara M, Kikukawa T, Miyauchi S, Yamaguchi M, Tero A, Takagi S, Nakagaki T: Kinetic study of anti-viral ribavirin uptake mediated by hCNT3 and hENT1 in Xenopus laevis oocytes. Biophys Chem. 2010 Mar;147(1-2):59-65. Epub 2010 Jan 6. Pubmed
  2. Fukuchi Y, Furihata T, Hashizume M, Iikura M, Chiba K: Characterization of ribavirin uptake systems in human hepatocytes. J Hepatol. 2010 Apr;52(4):486-92. Epub 2010 Feb 4. Pubmed

2. Solute carrier family 28 member 3

Actions: substrate

Sodium-dependent, pyrimidine- and purine-selective. Involved in the homeostasis of endogenous nucleosides. Exhibits the transport characteristics of the nucleoside transport system cib or N3 subtype (N3/cib) (with marked transport of both thymidine and inosine). Employs a 2:1 sodium/nucleoside ratio. Also able to transport gemcitabine, 3'-azido-3'-deoxythymidine (AZT), ribavirin and 3-deazauridine

UniProt ID: Q9HAS3 Link_out
Gene: SLC28A3 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Yamamoto T, Sugawara M, Kikukawa T, Miyauchi S, Yamaguchi M, Tero A, Takagi S, Nakagaki T: Kinetic study of anti-viral ribavirin uptake mediated by hCNT3 and hENT1 in Xenopus laevis oocytes. Biophys Chem. 2010 Mar;147(1-2):59-65. Epub 2010 Jan 6. Pubmed
Comments
Drug created on June 13, 2005 07:24 / Updated on August 12, 2011 08:18

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.