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Identification
NameTazarotene
Accession NumberDB00799  (APRD01246)
Typesmall molecule
Groupsapproved, investigational
Description

Tazarotene (marketed as Tazorac®, Avage® and Zorac®) is a prescription topical retinoid sold as a cream or gel. This medication is approved for treatment of psoriasis, acne, and sun damaged skin (photodamage). [Wikipedia]

Structure
Thumb
Synonyms
SynonymLanguageCode
TazaroteneNot AvailableINN, USAN
SaltsNot Available
Brand names
NameCompany
TazoracNot Available
ZoracNot Available
Brand mixturesNot Available
Categories
CAS number118292-40-3
WeightAverage: 351.462
Monoisotopic: 351.129299611
Chemical FormulaC21H21NO2S
InChI KeyInChIKey=OGQICQVSFDPSEI-UHFFFAOYSA-N
InChI
InChI=1S/C21H21NO2S/c1-4-24-20(23)16-7-9-17(22-14-16)8-5-15-6-10-19-18(13-15)21(2,3)11-12-25-19/h6-7,9-10,13-14H,4,11-12H2,1-3H3
IUPAC Name
ethyl 6-[2-(4,4-dimethyl-3,4-dihydro-2H-1-benzothiopyran-6-yl)ethynyl]pyridine-3-carboxylate
SMILES
CCOC(=O)C1=CN=C(C=C1)C#CC1=CC2=C(SCCC2(C)C)C=C1
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassLipids
ClassPrenol Lipids
SubclassRetinoids
Direct parentRetinoids
Alternative parentsThiochromanes; Pyridinecarboxylic Acids; Thiopyrans; Benzene and Substituted Derivatives; Carboxylic Acid Esters; Dialkyl Ethers; Enolates; Thioethers; Polyamines
Substituentsthiochromane; pyridine carboxylic acid; pyridine carboxylic acid or derivative; pyridine; thiopyran; benzene; carboxylic acid ester; enolate; thioether; polyamine; ether; dialkyl ether; carboxylic acid derivative; organonitrogen compound
Classification descriptionThis compound belongs to the retinoids. These are compounds that are related to vitamin A, especially retinol.
Pharmacology
IndicationUsed to treat psoriasis, acne and sun damaged skin (photodamage).
PharmacodynamicsTazarotene is a prodrug and a member of the acetylenic class of retinoids. Following topical application, tazarotene undergoes esterase hydrolysis to form its active metabolite, tazarotenic acid. When treating acne tazarotene may be taken in conjunction with an oral antibiotic. Tazarotene has been shown in peer-reviewed double blinded studies to reduce: mottling and hyperpigmentation, sallowness, fine wrinkling and coarse wrinkling in sun damaged skin. Histological studies have shown that long term (greater than 1 year) use of Tazarotene is associated with a significant reduction in atypical melanocytes and keratocytes - cells considered to be precursors of skin cancer. Some studies have shown long term use of Tazarotene to be associated with increased collagen production and better organization of skin collagen bundles.
Mechanism of actionAlthough the exact mechanism of tazarotene action is not known, studies have shown that the active form of the drug (tazarotenic acid) binds to all three members of the retinoic acid receptor (RAR) family: RARa, RARb, and RARg, but shows relative selectivity for RARb, and RARg and may modify gene expression. It also has affinity for RXR receptors.
AbsorptionMinimal systemic absorption of tazarotene occurs due to its rapid metabolism in the skin to the active metabolite, tazarotenic acid, which can be systemically absorbed and further metabolized. Gender had no influence on the systemic bioavailability of tazarotenic acid.
Volume of distributionNot Available
Protein bindingThe active form of the drug, tazarotenic acid, is highly bound to plasma proteins (>99%).
Metabolism

Undergoes esterase hydrolysis in skin to form its active metabolite, tazarotenic acid. Tazarotenic acid is further metabolized in skin and, after systemic absorption, hepatically metabolized to sulfoxides, sulfones, and other polar products for elimination.

SubstrateEnzymesProduct
Tazarotene
    Tazarotenic acidDetails
    Route of eliminationTazarotene and tazarotenic acid were metabolized to sulfoxides, sulfones and other polar metabolites which were eliminated through urinary and fecal pathways.
    Half lifeThe half-life of the active form of the drug, tazarotenic acid, is approximately 18 hours in normal and psoriatic patients.
    ClearanceNot Available
    ToxicityExcessive topical use may lead to marked redness, peeling, or discomfort. Oral ingestion of the drug may affect liver function causing hypertriglyceridemia. Other symptoms may include conjunctival irritation, hair loss, headache, edema, fatigue, dermatitis, nausea, and visual disturbances. Oral administration of this material to rats and rabbits at doses of 0.20 mg/kg/day (rabbits) and 0.25 mg/kg/day (rats) resulted in developmental toxicity. A no effect level of 0.05 mg/kg/day was established. Similar teratogenic effects have been reported for other retinoid compounds.
    Affected organisms
    • Humans and other mammals
    PathwaysNot Available
    SNP Mediated EffectsNot Available
    SNP Mediated Adverse Drug ReactionsNot Available
    ADMET
    Predicted ADMET features
    Property Value Probability
    Human Intestinal Absorption + 0.9936
    Blood Brain Barrier + 0.9675
    Caco-2 permeable + 0.5233
    P-glycoprotein substrate Substrate 0.5758
    P-glycoprotein inhibitor I Inhibitor 0.5422
    P-glycoprotein inhibitor II Non-inhibitor 0.5926
    Renal organic cation transporter Non-inhibitor 0.8219
    CYP450 2C9 substrate Non-substrate 0.7308
    CYP450 2D6 substrate Non-substrate 0.7687
    CYP450 3A4 substrate Substrate 0.5187
    CYP450 1A2 substrate Inhibitor 0.6172
    CYP450 2C9 substrate Inhibitor 0.6385
    CYP450 2D6 substrate Non-inhibitor 0.8531
    CYP450 2C19 substrate Inhibitor 0.6586
    CYP450 3A4 substrate Non-inhibitor 0.6387
    CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.6124
    Ames test Non AMES toxic 0.8154
    Carcinogenicity Non-carcinogens 0.8925
    Biodegradation Not ready biodegradable 0.9946
    Rat acute toxicity 2.5435 LD50, mol/kg Not applicable
    hERG inhibition (predictor I) Weak inhibitor 0.9968
    hERG inhibition (predictor II) Non-inhibitor 0.7757
    Pharmacoeconomics
    Manufacturers
    • Allergan inc
    Packagers
    Dosage forms
    FormRouteStrength
    CreamTopical
    GelTopical
    Prices
    Unit descriptionCostUnit
    Tazorac 0.1% Gel 100 gm Tube638.75USDtube
    Tazorac 0.05% Gel 100 gm Tube601.14USDtube
    Tazorac 60 gm Tube .1% 60 gm Tube383.22USDtube
    Tazorac 60 gm Tube .05% 60 gm Tube360.72USDtube
    Tazorac 0.1% Gel 30 gm Tube191.64USDtube
    Tazorac 30 gm Tube .1% 30 gm Tube191.64USDtube
    Tazorac 0.05% Cream 30 gm Tube180.39USDtube
    Tazorac 0.05% Gel 30 gm Tube180.39USDtube
    Tazorac 0.1% cream5.59USDg
    Tazorac 0.05% cream5.26USDg
    Tazorac 0.05 % Gel1.49USDg
    Tazorac 0.1 % Gel1.49USDg
    DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
    Patents
    CountryPatent NumberApprovedExpires (estimated)
    United States59143341994-06-072014-06-07
    United States50895091994-06-132011-06-13
    Canada21917732004-08-102015-08-10
    Properties
    Statesolid
    Experimental Properties
    PropertyValueSource
    water solubilitySolubleNot Available
    logP5.6Not Available
    Predicted Properties
    PropertyValueSource
    water solubility7.50e-04 g/lALOGPS
    logP5.15ALOGPS
    logP5.22ChemAxon
    logS-5.7ALOGPS
    pKa (strongest basic)1.23ChemAxon
    physiological charge0ChemAxon
    hydrogen acceptor count2ChemAxon
    hydrogen donor count0ChemAxon
    polar surface area39.19ChemAxon
    rotatable bond count5ChemAxon
    refractivity97.88ChemAxon
    polarizability40.31ChemAxon
    number of rings3ChemAxon
    bioavailability1ChemAxon
    rule of fiveNoChemAxon
    Ghose filterYesChemAxon
    Veber's ruleYesChemAxon
    MDDR-like ruleNoChemAxon
    Spectra
    SpectraNot Available
    References
    Synthesis Reference

    Samuele Frigoli, Claudio Fuganti, Stefano Serra, Francesco Pizzocaro, Angelo Bedeschi, Paolo Tubertini, “Process for the preparation of Tazarotene.” U.S. Patent US20060205950, issued September 14, 2006.

    US20060205950
    General ReferenceNot Available
    External Links
    ResourceLink
    KEGG DrugD01132
    KEGG CompoundC12531
    PubChem Compound5381
    PubChem Substance46508992
    ChemSpider5188
    ChEBI32184
    ChEMBLCHEMBL1657
    Therapeutic Targets DatabaseDAP000462
    PharmGKBPA164746821
    Drug Product Database2243894
    RxListhttp://www.rxlist.com/cgi/generic3/avage.htm
    Drugs.comhttp://www.drugs.com/cdi/tazarotene-cream.html
    PDRhealthhttp://www.pdrhealth.com/drug_info/rxdrugprofiles/drugs/taz1429.shtml
    WikipediaTazarotene
    ATC CodesD05AX05
    AHFS Codes
    • 84:92.00
    PDB EntriesNot Available
    FDA labelshow(90.3 KB)
    MSDSshow(25.7 KB)
    Interactions
    Drug InteractionsSearched, but no interactions found.
    Food InteractionsNot Available

    1. Retinoic acid receptor alpha

    Kind: protein

    Organism: Human

    Pharmacological action: yes

    Actions: agonist

    Components

    Name UniProt ID Details
    Retinoic acid receptor alpha P10276 Details

    References:

    1. Baumann L, Vujevich J, Halem M, Martin LK, Kerdel F, Lazarus M, Pacheco H, Black L, Bryde J: Open-label pilot study of alitretinoin gel 0.1% in the treatment of photoaging. Cutis. 2005 Jul;76(1):69-73. Pubmed
    2. Chandraratna RA: Tazarotene—first of a new generation of receptor-selective retinoids. Br J Dermatol. 1996 Oct;135 Suppl 49:18-25. Pubmed
    3. Yen A, Fenning R, Chandraratna R, Walker P, Varvayanis S: A retinoic acid receptor beta/gamma-selective prodrug (tazarotene) plus a retinoid X receptor ligand induces extracellular signal-regulated kinase activation, retinoblastoma hypophosphorylation, G0 arrest, and cell differentiation. Mol Pharmacol. 2004 Dec;66(6):1727-37. Epub 2004 Sep 21. Pubmed
    4. Meder W, Wendland M, Busmann A, Kutzleb C, Spodsberg N, John H, Richter R, Schleuder D, Meyer M, Forssmann WG: Characterization of human circulating TIG2 as a ligand for the orphan receptor ChemR23. FEBS Lett. 2003 Dec 18;555(3):495-9. Pubmed
    5. Wang Q, Lee D, Sysounthone V, Chandraratna RAS, Christakos S, Korah R, Wieder R: 1,25-dihydroxyvitamin D3 and retonic acid analogues induce differentiation in breast cancer cells with function- and cell-specific additive effects. Breast Cancer Res Treat. 2001 May;67(2):157-68. Pubmed
    6. Nagpal S, Chandraratna RA: Recent developments in receptor-selective retinoids. Curr Pharm Des. 2000 Jun;6(9):919-31. Pubmed

    2. Retinoic acid receptor RXR-beta

    Kind: protein

    Organism: Human

    Pharmacological action: yes

    Actions: agonist

    Components

    Name UniProt ID Details
    Retinoic acid receptor RXR-beta P28702 Details

    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. Nagpal S, Chandraratna RA: Recent developments in receptor-selective retinoids. Curr Pharm Des. 2000 Jun;6(9):919-31. Pubmed

    3. Retinoic acid receptor gamma

    Kind: protein

    Organism: Human

    Pharmacological action: yes

    Actions: agonist

    Components

    Name UniProt ID Details
    Retinoic acid receptor gamma P13631 Details

    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. Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE: The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. Pubmed
    4. Arechalde A, Saurat JH: Management of psoriasis: the position of retinoid drugs. BioDrugs. 2000 May;13(5):327-33. Pubmed
    5. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

    4. Retinoic acid receptor beta

    Kind: protein

    Organism: Human

    Pharmacological action: yes

    Actions: agonist

    Components

    Name UniProt ID Details
    Retinoic acid receptor beta P10826 Details

    References:

    1. Jones PH, Burnett RD, Fainaru I, Nadolny P, Walker P, Yu Z, Tang-Liu D, Ganesan TS, Talbot DC, Harris AL, Rustin GJ: A phase 1 study of tazarotene in adults with advanced cancer. Br J Cancer. 2003 Sep 1;89(5):808-15. Pubmed
    2. Orlandi A, Bianchi L, Costanzo A, Campione E, Giusto Spagnoli L, Chimenti S: Evidence of increased apoptosis and reduced proliferation in basal cell carcinomas treated with tazarotene. J Invest Dermatol. 2004 Apr;122(4):1037-41. Pubmed
    3. Chandraratna RA: Tazarotene—first of a new generation of receptor-selective retinoids. Br J Dermatol. 1996 Oct;135 Suppl 49:18-25. Pubmed
    4. Arechalde A, Saurat JH: Management of psoriasis: the position of retinoid drugs. BioDrugs. 2000 May;13(5):327-33. Pubmed

    1. Cytochrome P450 2C8

    Kind: protein

    Organism: Human

    Pharmacological action: unknown

    Actions: substrate

    Components

    Name UniProt ID Details
    Cytochrome P450 2C8 P10632 Details

    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 September 16, 2013 17:12