Peginterferon alfa-2b

Identification

Summary

Peginterferon alfa-2b is a purified form of human interferon used to stimulate the innate antiviral response in the treatment of hepatitis B and C, genital warts, and some cancers.

Brand Names
Pegintron, Sylatron
Generic Name
Peginterferon alfa-2b
DrugBank Accession Number
DB00022
Background

Peginterferon alfa-2b is a form of recombinant interferon used as part of combination therapy to treat chronic Hepatitis C, an infectious liver disease caused by infection with Hepatitis C Virus (HCV). HCV is a single-stranded RNA virus that is categorized into nine distinct genotypes, with genotype 1 being the most common in the United States, and affecting 72% of all chronic HCV patients 3. Treatment options for chronic Hepatitis C have advanced significantly since 2011, with the development of Direct Acting Antivirals (DAAs) resulting in less use of Peginterferon alfa-2b. Peginterferon alfa-2b is derived from the alfa-2b moeity of recombinant human interferon and acts by binding to human type 1 interferon receptors. Activation and dimerization of this receptor induces the body's innate antiviral response by activating the janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. Use of Peginterferon alfa-2b is associated with a wide range of severe adverse effects including the aggravation and development of endocrine and autoimmune disorders, retinopathies, cardiovascular and neuropsychiatric complications, and increased risk of hepatic decompensation in patients with cirrhosis. The use of Peginterferon alfa-2b has largely declined since newer interferon-free antiviral therapies have been developed.

In a joint recommendation published in 2016, the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) no longer recommend Peginterferon alfa-2b for the treatment of Hepatitis C 2. Peginterferon alfa-2b was used alongside Ribavirin(https://go.drugbank.com/drugs/DB00811) with the intent to cure, or achieve a sustained virologic response (SVR), after 48 weeks of therapy. SVR and eradication of HCV infection is associated with significant long-term health benefits including reduced liver-related damage, improved quality of life, reduced incidence of Hepatocellular Carcinoma, and reduced all-cause mortality 1.

Peginterferon alfa-2b is available as a variable dose injectable product (tradename Pegintron) used for the treatment of chronic Hepatitis C. Approved in 2001 by the FDA, Pegintron is indicated for the treatment of HCV with Ribavirin or other antiviral drugs Label. When combined together, Peginterferon alfa-2b and Ribavirin have been shown to achieve a SVR between 41% for genotype 1 and 75% for genotypes 2-6 after 48 weeks of treatment.

Type
Biotech
Groups
Approved
Biologic Classification
Protein Based Therapies
Interferons
Protein Structure
Protein Chemical Formula
Not Available
Protein Average Weight
31000.0 Da
Sequences
>DB00022 sequence
CDLPQTHSLGSRRTLMLLAQMRRISLFSCLKDRHDFGFPQEEFGNQFQKAETIPVLHEMI
QQIFNLFSTKDSSAAWDETLLDKFYTELYQQLNDLEACVIQGVGVTETPLMKEDSILAVR
KYFQRITLYLKEKKYSPCAWEVVRAEIMRSFSLSTNLQESLRSKE
Download FASTA Format
Synonyms
  • Peginterferon alfa-2b

Pharmacology

Indication

Peginterferon alfa-2b is indicated for the treatment of HCV in combination with Ribavirin and a NS3/4A protease inhibitor for genotype 1 or without a NS3/4A protease inhibitor for genotypes 2-6 Label. May be used as a monotherapy in patients with contraindications to or significant intolerance to other anti-viral therapies.

It is also indicated for the adjuvant treatment of melanoma with microscopic or gross nodal involvement within 84 days of definitive surgical resection, including complete lymphadenectomy.4

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Treatment ofChronic hepatitis c virus (hcv) infection••••••••••••••••••••••••••• ••••••••••••••••••
Treatment ofChronic hepatitis c virus (hcv) infection••••••••••••••••••••••• ••••• •••••••• •••••••• ••• •••• ••••••••• •• ••••••••••••••••••••••••
Used in combination to treatChronic hepatitis c virus (hcv) infectionRegimen in combination with: Ribavirin (DB00811)••••••••••••••••••••••• ••••••••••••••••••
Used in combination to treatChronic hepatitis c virus (hcv) infectionRegimen in combination with: Ribavirin (DB00811)••••••••••••••••••••••••••
Used in combination to treatChronic hepatitis c virus (hcv) infectionRegimen in combination with: Ribavirin (DB00811)•••••••••••••••••••• •••••••• • ••••••••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

Peginterferon alfa-2b inhibits viral replication in infected cells, suppresses cell proliferation, induces apoptosis, and exerts an anti-angiogenic effect Label. Exerts immunomodulatory effects such as enhancement of the phagocytic activity of macrophages, activation of NK cells, stimulation of cytotoxic T-lymphocytes, and the upregulation of the Th1 T-helper cell subset. Also increases concentrations of effector proteins such as serum neopterin and 2'5' oligoadenylate synthetase, raises body temperature, and causes reversible decreases in leukocyte and platelet counts.

Mechanism of action

Peginterferon alfa-2b is derived from recombinant human interferon's alfa-2b moeity Label. It binds to and activates human type 1 interferon receptors causing them to dimerize. This activates the JAK/STAT pathway. Activation of the JAK/STAT pathway increases expression of multiple genes in multiple tissues involved in the innate antiviral response. Peginterferon alfa-2b may also acitvate the nuclear factor κB pathway.

TargetActionsOrganism
AInterferon alpha/beta receptor 1
agonist
Humans
AInterferon alpha/beta receptor 2
agonist
Humans
Absorption

Peginterferon alfa-2b reaches peak plasma concentration 15-44 hours after subcutaneous administration Label. The mean absorption half-life is 4.6 hours. After multiple doses the bioavailability of Peginterferon alfa-2b increases with trough concentrations at week 48 3-fold higher than those at week 4.

Volume of distribution

Not Available

Protein binding

Not Available

Metabolism
Not Available
Route of elimination

Renal elimination accounts for 30% of Peginterferon alfa-2b elimination Label.

Half-life

The mean half-life of elimination of Peginterferon alfa-2b is 40 hours in a range of 22-60 hours Label.

Clearance

The estimated apparent clearance of Peginterferon alfa-2b is 22 milliters per hour per kilogram Label.

Adverse Effects
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Toxicity

Peginterferon alfa-2b may manifest neuropsychiatric complications include suicide, suicidal ideation, homicidal ideation, depression, relapse of drug addiction, and drug overdose Label. Hypertension, supraventricular arrhythmias, chest pain, and myocardial infarction have been observed in patients using Peginterferon alfa-2b. Peginterferon alfa-2b may produce myelosuppression as well as the development or aggravation of autoimmune disorders including myositis, hepatitis, thrombotic thrombocytopenic purpura, idiopathic thrombocytopenic purpura, psoriasis, rheumatoid arthritis, interstitial nephritis, thyroiditis, and systemic lupus erythematosus. Peginterferon alfa-2b causes or aggravates hypothyroidism and hyperthyroidism. Hyperglycemia, hypoglycemia, and diabetes mellitus have been observed to develop in patients treated with Peginterferon alfa-2b. Peginterferon alfa-2b may decrease or produce loss of vision, retinopathy including macular edema, retinal artery or vein thrombosis, retinal hemorrhages and cotton wool spots, optic neuritis, papilledema and serous retinal detachment. Peginterferon mayy be related to increased ischemic and hemorrhagic cerebrovascular events. Patients with cirrhosis on Peginterferon alfa-2b are at risk of hepatic decompensation. Dyspnea, pulmonary infiltrates, pneumonia, bronchiolitis obliterans, interstitial pneumonitis, pulmonary hypertension and sarcoidosis may be induced or aggravated by Peginterferon alfa-2b. Serious and severe infections (bacterial, viral, or fungal) have been reported during treatment with Peginterferon alfa-2b. Ulcerative and hemorrhagic/ischemic colitis have been observed within 12 weeks of starting Peginterferon alfa-2b treatment. Pancreatitis and peripheral nephropathy have also been reported. Peginterferon alfa-2b is associated with growth inhibition in pediatric patients. Use of Peginterferon alfa-2b while pregant may result in delopmental abnormalities or death of the fetus.

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Interacting Gene/EnzymeAllele nameGenotype(s)Defining Change(s)Type(s)DescriptionDetails
Interferon lambda-3---(T;T) / (C;T) / (G;G) / (G;T)C > TEffect Directly StudiedPatients with this genotype in IFNL3 have a reduced likelihood of achieving sustained virologic response to peginterferon alfa-2b therapy.Details

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
AbataceptThe risk or severity of adverse effects can be increased when Peginterferon alfa-2b is combined with Abatacept.
AbciximabThe risk or severity of bleeding can be increased when Abciximab is combined with Peginterferon alfa-2b.
AbrocitinibThe metabolism of Abrocitinib can be increased when combined with Peginterferon alfa-2b.
AcebutololThe metabolism of Acebutolol can be decreased when combined with Peginterferon alfa-2b.
AcenocoumarolThe serum concentration of Acenocoumarol can be increased when it is combined with Peginterferon alfa-2b.
Food Interactions
  • Limit caffeine intake. Peginterferon alfa-2b can increase the serum levels of caffeine by inhibiting its metabolism through the CYP1A2 pathway.

Products

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Active Moieties
NameKindUNIICASInChI Key
Interferon alfa-2bunknown43K1W2T1M698530-12-2Not applicable
International/Other Brands
PEG-Intron (Schering Corp)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
PegintronInjection, powder, for solution120 mcgSubcutaneousMerck Sharp & Dohme B.V.2021-02-112021-06-03EU flag
PegintronInjection, powder, for solution80 mcgSubcutaneousMerck Sharp & Dohme B.V.2021-02-112021-06-03EU flag
PegintronInjection, powder, for solution50 mcgSubcutaneousMerck Sharp & Dohme B.V.2021-02-112021-06-03EU flag
PegintronInjection, powder, for solution; Kit120 ug/0.5mLSubcutaneousMerck Sharp & Dohme Corp.2014-08-11Not applicableUS flag
PegintronInjection, powder, for solution150 mcgSubcutaneousMerck Sharp & Dohme B.V.2021-02-112021-06-03EU flag
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
PegetronPeginterferon alfa-2b (50 mcg / 0.5 mL) + Ribavirin (200 mg / cap)Capsule; Powder, for solutionOral; SubcutaneousMerck Ltd.2002-08-132017-04-04Canada flag
PegetronPeginterferon alfa-2b (100 mcg / 0.5 mL) + Ribavirin (200 mg / cap)Capsule; Powder, for solutionOral; SubcutaneousMerck Ltd.2002-08-132013-01-23Canada flag
PegetronPeginterferon alfa-2b (150 mcg / 0.5 mL) + Ribavirin (200 mg / cap)Capsule; Powder, for solutionOral; SubcutaneousMerck Ltd.2004-09-172017-10-05Canada flag
PegetronPeginterferon alfa-2b (80 mcg / 0.5 mL) + Ribavirin (200 mg / cap)Capsule; Powder, for solutionOral; SubcutaneousMerck Ltd.2004-09-172017-10-05Canada flag
PegetronPeginterferon alfa-2b (120 mcg / 0.5 mL) + Ribavirin (200 mg / cap)Capsule; Powder, for solutionOral; SubcutaneousMerck Ltd.2004-09-172017-10-05Canada flag

Categories

ATC Codes
L03AB10 — Peginterferon alfa-2bL03AB60 — Peginterferon alfa-2b, combinations
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
Not Available
Kingdom
Organic Compounds
Super Class
Organic Acids
Class
Carboxylic Acids and Derivatives
Sub Class
Amino Acids, Peptides, and Analogues
Direct Parent
Peptides
Alternative Parents
Not Available
Substituents
Not Available
Molecular Framework
Not Available
External Descriptors
Not Available
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
G8RGG88B68
CAS number
215647-85-1

References

General References
  1. Myers RP, Shah H, Burak KW, Cooper C, Feld JJ: An update on the management of chronic hepatitis C: 2015 Consensus guidelines from the Canadian Association for the Study of the Liver. Can J Gastroenterol Hepatol. 2015 Jan-Feb;29(1):19-34. Epub 2015 Jan 13. [Article]
  2. Bagaglio S, Uberti-Foppa C, Morsica G: Resistance Mechanisms in Hepatitis C Virus: implications for Direct-Acting Antiviral Use. Drugs. 2017 May 12. doi: 10.1007/s40265-017-0753-x. [Article]
  3. American Association for the Study of Liver Diseases; Infectious Diseases Society of America. HCV guidance. http://hcvguidelines.org. Accessed June 12, 2017. [Link]
  4. FDA Approved Drug Products: SYLATRON (peginterferon alfa-2b) for injection, for subcutaneous use (December 2018) [Link]
UniProt
P01563
PubChem Substance
46506669
RxNav
253453
ChEMBL
CHEMBL1201561
Therapeutic Targets Database
DAP001279
PharmGKB
PA164784024
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Peginterferon_alfa-2b
FDA label
Download (1.69 MB)

Clinical Trials

Clinical Trials

Pharmacoeconomics

Manufacturers
Not Available
Packagers
  • Physicians Total Care Inc.
  • Schering Corp.
  • Schering-Plough Inc.
  • Vetter Pharma Fertigung GmbH and Co. KG
Dosage Forms
FormRouteStrength
Injection, powder, for solutionSubcutaneous100 mcg/0.5ml
Injection, powder, for solutionSubcutaneous120 mcg/0.5ml
Injection, powder, for solutionSubcutaneous150 mcg/0.5ml
Injection, powder, for solutionSubcutaneous50 mcg/0.5ml
Injection, powder, for solutionSubcutaneous80 mcg/0.5ml
Capsule; powder, for solutionOral; Subcutaneous
Injection, powder, for solution; kitSubcutaneous120 ug/0.5mL
Injection, powder, for solution; kitSubcutaneous150 ug/0.5mL
Injection, powder, for solution; kitSubcutaneous50 ug/0.5mL
Injection, powder, for solution; kitSubcutaneous80 ug/0.5mL
Injection, powder, lyophilized, for solutionSubcutaneous120 ug/0.5mL
Injection, powder, lyophilized, for solutionSubcutaneous150 ug/0.5mL
Injection, powder, lyophilized, for solutionSubcutaneous50 ug/0.5mL
Injection, powder, lyophilized, for solutionSubcutaneous80 ug/0.5mL
KitSubcutaneous120 ug/0.5mL
KitSubcutaneous150 ug/0.5mL
KitSubcutaneous50 ug/0.5mL
KitSubcutaneous80 ug/0.5mL
Injection, solution100 mcg
Injection, solution120 mcg
Injection, solution150 mcg
Injection, solution50 mcg
Injection, solution80 mcg
Injection, powder, lyophilized, for solutionSubcutaneous50 mcg
KitSubcutaneous120 ug/0.1mL
KitSubcutaneous40 ug/0.1mL
KitSubcutaneous60 ug/0.1mL
Powder, for solutionSubcutaneous118.4 mcg / vial
Powder, for solutionSubcutaneous177.6 mcg / vial
Powder, for solutionSubcutaneous222 mcg / vial
Powder, for solutionSubcutaneous74 mcg / vial
Injection, powder, for solutionSubcutaneous100 MCG
Injection, powder, for solutionSubcutaneous120 MCG
Injection, powder, for solutionSubcutaneous150 MCG
Injection, powder, for solutionSubcutaneous50 MCG
Injection, powder, for solutionSubcutaneous80 MCG
Powder100 mcg/1vial
Prices
Unit descriptionCostUnit
Peg-Intron Redipen Pak 4 4 50 mcg/0.5ml Kit Box2428.8USD kit
Peg-Intron Redipen 150 mcg/0.5ml Kit702.87USD kit
Peg-Intron 150 mcg Kit671.74USD kit
Peg-Intron Redipen 120 mcg/0.5ml Kit669.39USD kit
Peg-Intron redipen 150 mcg640.61USD redipen
Peg-Intron redipen 150 mcg 4pk640.6USD redipen
Peg-Intron 120 mcg Kit639.74USD kit
Peg-Intron Redipen 80 mcg/0.5ml Kit637.49USD kit
Peg-Intron redipen 120 mcg610.09USD redipen
Peg-Intron 80 mcg Kit609.26USD kit
Peg-Intron 50 mcg/0.5ml Kit607.19USD kit
Peg-Intron redipen 80 mcg581.02USD redipen
Peg-Intron 50 mcg kit553.4USD kit
Peg-Intron redipen 50 mcg553.4USD redipen
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
CA1341567No2008-02-192025-02-19Canada flag
CA2329474No2002-02-262016-10-31Canada flag

Properties

State
Liquid
Experimental Properties
PropertyValueSource
melting point (°C)61 °CBeldarrain, A. et al., Biochemistry 38:7865-7873 (1999)
isoelectric point5.99Not Available

Targets

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insights and accelerate drug research.
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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
General Function
Type i interferon receptor activity
Specific Function
Associates with IFNAR2 to form the type I interferon receptor. Receptor for interferons alpha and beta. Binding to type I IFNs triggers tyrosine phosphorylation of a number of proteins including JA...
Gene Name
IFNAR1
Uniprot ID
P17181
Uniprot Name
Interferon alpha/beta receptor 1
Molecular Weight
63524.81 Da
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. [Article]
  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. [Article]
  3. Dhalluin C, Ross A, Huber W, Gerber P, Brugger D, Gsell B, Senn H: Structural, kinetic, and thermodynamic analysis of the binding of the 40 kDa PEG-interferon-alpha2a and its individual positional isomers to the extracellular domain of the receptor IFNAR2. Bioconjug Chem. 2005 May-Jun;16(3):518-27. [Article]
  4. Ishii K, Shinohara M, Sawa M, Kogame M, Higami K, Sano M, Morita T, Sumino Y: Interferon alpha receptor 2 expression by peripheral blood monocytes in patients with a high viral load of hepatitis C virus genotype 1 showing substitution of amino Acid 70 in the core region. Intervirology. 2010;53(2):105-10. doi: 10.1159/000264200. Epub 2009 Dec 3. [Article]
  5. Yano H, Ogasawara S, Momosaki S, Akiba J, Kojiro S, Fukahori S, Ishizaki H, Kuratomi K, Basaki Y, Oie S, Kuwano M, Kojiro M: Growth inhibitory effects of pegylated IFN alpha-2b on human liver cancer cells in vitro and in vivo. Liver Int. 2006 Oct;26(8):964-75. [Article]
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
General Function
Type i interferon receptor activity
Specific Function
Associates with IFNAR1 to form the type I interferon receptor. Receptor for interferons alpha and beta. Involved in IFN-mediated STAT1, STAT2 and STAT3 activation. Isoform 1 and isoform 2 are direc...
Gene Name
IFNAR2
Uniprot ID
P48551
Uniprot Name
Interferon alpha/beta receptor 2
Molecular Weight
57758.24 Da
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. [Article]
  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. [Article]
  3. Dhalluin C, Ross A, Huber W, Gerber P, Brugger D, Gsell B, Senn H: Structural, kinetic, and thermodynamic analysis of the binding of the 40 kDa PEG-interferon-alpha2a and its individual positional isomers to the extracellular domain of the receptor IFNAR2. Bioconjug Chem. 2005 May-Jun;16(3):518-27. [Article]
  4. Ishii K, Shinohara M, Sawa M, Kogame M, Higami K, Sano M, Morita T, Sumino Y: Interferon alpha receptor 2 expression by peripheral blood monocytes in patients with a high viral load of hepatitis C virus genotype 1 showing substitution of amino Acid 70 in the core region. Intervirology. 2010;53(2):105-10. doi: 10.1159/000264200. Epub 2009 Dec 3. [Article]
  5. Yano H, Ogasawara S, Momosaki S, Akiba J, Kojiro S, Fukahori S, Ishizaki H, Kuratomi K, Basaki Y, Oie S, Kuwano M, Kojiro M: Growth inhibitory effects of pegylated IFN alpha-2b on human liver cancer cells in vitro and in vivo. Liver Int. 2006 Oct;26(8):964-75. [Article]
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
Curator comments
The FDA label states that single doses of this agent may not affect the CYP1A2 enzyme, however, the effect of multiple doses has not been studied.
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 un...
Gene Name
CYP1A2
Uniprot ID
P05177
Uniprot Name
Cytochrome P450 1A2
Molecular Weight
58293.76 Da
References
  1. Gupta SK, Kolz K, Cutler DL: Effects of multiple-dose pegylated interferon alfa-2b on the activity of drug-metabolizing enzymes in persons with chronic hepatitis C. Eur J Clin Pharmacol. 2011 Jun;67(6):591-9. doi: 10.1007/s00228-010-0972-5. Epub 2010 Dec 16. [Article]
  2. Peg-interferon alfa-2b FDA label [File]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic...
Gene Name
CYP2D6
Uniprot ID
P10635
Uniprot Name
Cytochrome P450 2D6
Molecular Weight
55768.94 Da
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inducer
General Function
Steroid 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 oxidizes a variety of structurally un...
Gene Name
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
References
  1. Brennan BJ, Xu ZX, Grippo JF: Effect of peginterferon alfa-2a (40KD) on cytochrome P450 isoenzyme activity. Br J Clin Pharmacol. 2013 Feb;75(2):497-506. doi: 10.1111/j.1365-2125.2012.04373.x. [Article]
  2. Aids info document [Link]
  3. Sylatron FDA label [File]

Drug created at June 13, 2005 13:24 / Updated at March 18, 2024 16:48