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Identification
NameRofecoxib
Accession NumberDB00533  (APRD00151)
Typesmall molecule
Groupsinvestigational, withdrawn
Description

On September 30, 2004, Merck voluntarily withdrew rofecoxib from the market because of concerns about increased risk of heart attack and stroke associated with long-term, high-dosage use.

Structure
Thumb
SynonymsNot Available
SaltsNot Available
Brand names
NameCompany
VioxxNot Available
Brand mixturesNot Available
CategoriesNot Available
CAS number162011-90-7
WeightAverage: 314.356
Monoisotopic: 314.061279626
Chemical FormulaC17H14O4S
InChI KeyInChIKey=RZJQGNCSTQAWON-UHFFFAOYSA-N
InChI
InChI=1S/C17H14O4S/c1-22(19,20)14-9-7-12(8-10-14)15-11-21-17(18)16(15)13-5-3-2-4-6-13/h2-10H,11H2,1H3
IUPAC Name
4-(4-methanesulfonylphenyl)-3-phenyl-2,5-dihydrofuran-2-one
SMILES
CS(=O)(=O)C1=CC=C(C=C1)C1=C(C(=O)OC1)C1=CC=CC=C1
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassPhenylpropanoids and Polyketides
ClassStilbenes
SubclassNot Available
Direct parentStilbenes
Alternative parentsBenzene and Substituted Derivatives; Butenolides; Sulfones; Sulfoxides; Carboxylic Acid Esters; Polyamines
Substituentsbenzene; 2-furanone; sulfone; sulfonyl; dihydrofuran; sulfoxide; carboxylic acid ester; polyamine; carboxylic acid derivative
Classification descriptionThis compound belongs to the stilbenes. These are organic compounds containing a 1,2-diphenylethylene moiety. Stilbenes (C6-C2-C6 ) are derived from the common phenylpropene (C6-C3) skeleton building block. The introduction of one or more hydroxyl groups to a phenyl ring lead to stilbenoids.
Pharmacology
IndicationFor the treatment of osteoarthritis, rheumatoid arthritis, acute pain in adults, and primary dysmenorrhea, as well as acute treatment of migraine attacks with or without auras.
PharmacodynamicsRofecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, is classified as a nonsteroidal anti-inflammatory drug (NSAID). Unlike celecoxib, rofecoxib lacks a sulfonamide chain and does not require CYP450 enzymes for metabolism. Like other NSAIDs, rofecoxib exhibits anti-inflammatory, analgesic, and antipyretic activity. NSAIDs appear to inhibit prostaglandin synthesis via the inhibition of cyclooxygenase (COX), which are responsible for catalyzing the formation of prostaglandins in the arachidonic acid pathyway. There are at least two isoenzymes, COX-1 and COX-2, that have been identified. Although the exact mechanisms have not been clearly established, NSAIDs exert their anti-inflammatory, analgesic, and antipyretic primarily through the inhibition of COX-2. The inhibition of COX-1 is principally responsible for the negative effects on the GI mucosa. As rofecoxib is selective for COX-2, it may be potentially associated with a decreased risk of certain adverse events, but more data is needed to fully evaulate the drug.
Mechanism of actionThe anti-inflammatory, analgesic, and antipyretic effects of NSAIDs appear to result from the inhibition of prostaglandin synthesis. Although the exact mechanism of action has not been determined, these effects appear to be mediated through the inhibition of the COX-2 isoenzyme at the sites of inflammation with subsequent reduction in the synthesis of certain prostaglandins from their arachidonic acid precursors. Rofecoxib selectively inhibits the cyclooxygenase-2 (COX-2) enzyme, which is important for the mediation of inflammation and pain. Unlike non-selective NSAIDs, rofecoxib does not inhibit platelet aggregation. It also has little to no affinity for COX-1.
AbsorptionThe mean oral bioavailability of rofecoxib at therapeutically recommended doses of 12.5, 25, and 50 mg is approximately 93%.
Volume of distributionNot Available
Protein binding87%
Metabolism

Hepatic. Metabolism of rofecoxib is primarily mediated through reduction by cytosolic enzymes. The principal metabolic products are the cis-dihydro and trans-dihydro derivatives of rofecoxib, which account for nearly 56% of recovered radioactivity in the urine. An additional 8.8% of the dose was recovered as the glucuronide of the hydroxy derivative, a product of oxidative metabolism. The biotransformation of rofecoxib and this metabolite is reversible in humans to a limited extent (< 5%). These metabolites are inactive as COX-1 or COX-2 inhibitors. Cytochrome P450 plays a minor role in metabolism of rofecoxib.

SubstrateEnzymesProduct
Rofecoxib
5-HydroxyrofecoxibDetails
Rofecoxib
Dihydro-5-hydroxyrofecoxibDetails
Rofecoxib
Rofecoxib-threo-3,4-dihydrohydroxy acidDetails
Rofecoxib
Rofecoxib-erythro-3,4-dihydrohydroxy acidDetails
Rofecoxib-erythro-3,4-dihydrohydroxy acid
    cis-DihydrorofecoxibDetails
    Rofecoxib-threo-3,4-dihydrohydroxy acid
      trans-DihydrorofecoxibDetails
      Dihydro-5-hydroxyrofecoxib
        Rofecoxib-threo-3,4-dihydrohydroxy acidDetails
        5-Hydroxyrofecoxib
        5-Hydroxyrofecoxib O-glucuronideDetails
        Route of eliminationNot Available
        Half life17 hours
        ClearanceNot Available
        ToxicityNo overdoses of rofecoxib were reported during clinical trials. Administration of single doses of rofecoxib 1000 mg to 6 healthy volunteers and multiple doses of 250 mg/day for 14 days to 75 healthy volunteers did not result in serious toxicity.
        Affected organisms
        • Humans and other mammals
        Pathways
        PathwayCategorySMPDB ID
        Rofecoxib Action PathwayDrug actionSMP00087
        SNP Mediated EffectsNot Available
        SNP Mediated Adverse Drug ReactionsNot Available
        ADMET
        Predicted ADMET features
        Property Value Probability
        Human Intestinal Absorption + 0.9938
        Blood Brain Barrier + 0.6296
        Caco-2 permeable - 0.5696
        P-glycoprotein substrate Non-substrate 0.7186
        P-glycoprotein inhibitor I Non-inhibitor 0.5401
        P-glycoprotein inhibitor II Non-inhibitor 0.922
        Renal organic cation transporter Non-inhibitor 0.7846
        CYP450 2C9 substrate Non-substrate 0.5807
        CYP450 2D6 substrate Non-substrate 0.9116
        CYP450 3A4 substrate Non-substrate 0.5941
        CYP450 1A2 substrate Inhibitor 0.5426
        CYP450 2C9 substrate Inhibitor 0.6668
        CYP450 2D6 substrate Non-inhibitor 0.889
        CYP450 2C19 substrate Inhibitor 0.6214
        CYP450 3A4 substrate Non-inhibitor 0.8508
        CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.7596
        Ames test Non AMES toxic 0.6152
        Carcinogenicity Non-carcinogens 0.5754
        Biodegradation Not ready biodegradable 0.7716
        Rat acute toxicity 2.4527 LD50, mol/kg Not applicable
        hERG inhibition (predictor I) Weak inhibitor 0.9848
        hERG inhibition (predictor II) Non-inhibitor 0.8932
        Pharmacoeconomics
        Manufacturers
        • Merck research laboratories div merck co inc
        Packagers
        Dosage forms
        FormRouteStrength
        SuspensionOral
        TabletOral
        PricesNot Available
        Patents
        CountryPatent NumberApprovedExpires (estimated)
        United States60638111997-11-062017-11-06
        United States54749951993-06-242013-06-24
        Properties
        Statesolid
        Experimental Properties
        PropertyValueSource
        water solubilityInsolubleNot Available
        logP3.2Not Available
        Predicted Properties
        PropertyValueSource
        water solubility1.06e-02 g/lALOGPS
        logP2.32ALOGPS
        logP2.56ChemAxon
        logS-4.5ALOGPS
        pKa (strongest acidic)14.84ChemAxon
        pKa (strongest basic)-7ChemAxon
        physiological charge0ChemAxon
        hydrogen acceptor count3ChemAxon
        hydrogen donor count0ChemAxon
        polar surface area60.44ChemAxon
        rotatable bond count3ChemAxon
        refractivity84.08ChemAxon
        polarizability31.74ChemAxon
        number of rings3ChemAxon
        bioavailability1ChemAxon
        rule of fiveYesChemAxon
        Ghose filterYesChemAxon
        Veber's ruleNoChemAxon
        MDDR-like ruleNoChemAxon
        Spectra
        SpectraNot Available
        References
        Synthesis ReferenceNot Available
        General Reference
        1. Bombardier C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R, Davis B, Day R, Ferraz MB, Hawkey CJ, Hochberg MC, Kvien TK, Schnitzer TJ: Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N Engl J Med. 2000 Nov 23;343(21):1520-8, 2 p following 1528. Pubmed
        2. Bresalier RS, Sandler RS, Quan H, Bolognese JA, Oxenius B, Horgan K, Lines C, Riddell R, Morton D, Lanas A, Konstam MA, Baron JA: Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med. 2005 Mar 17;352(11):1092-102. Epub 2005 Feb 15. Pubmed
        3. Curfman GD, Morrissey S, Drazen JM: Expression of concern reaffirmed. N Engl J Med. 2006 Mar 16;354(11):1193. Epub 2006 Feb 22. Pubmed
        4. Fitzgerald GA: Coxibs and cardiovascular disease. N Engl J Med. 2004 Oct 21;351(17):1709-11. Epub 2004 Oct 6. Pubmed
        5. Karha J, Topol EJ: The sad story of Vioxx, and what we should learn from it. Cleve Clin J Med. 2004 Dec;71(12):933-4, 936, 938-9. Pubmed
        6. Baron JA, Sandler RS, Bresalier RS, Lanas A, Morton DG, Riddell R, Iverson ER, Demets DL: Cardiovascular events associated with rofecoxib: final analysis of the APPROVe trial. Lancet. 2008 Nov 15;372(9651):1756-64. Epub 2008 Oct 14. Pubmed
        7. Matheson AJ, Figgitt DP: Rofecoxib: a review of its use in the management of osteoarthritis, acute pain and rheumatoid arthritis. Drugs. 2001;61(6):833-65. Pubmed
        8. Hillson JL, Furst DE: Rofecoxib. Expert Opin Pharmacother. 2000 Jul;1(5):1053-66. Pubmed
        External Links
        ResourceLink
        KEGG DrugD00568
        KEGG CompoundC07590
        PubChem Compound5090
        PubChem Substance46504787
        ChemSpider4911
        BindingDB22369
        ChEBI8887
        ChEMBL
        Therapeutic Targets DatabaseDAP001338
        PharmGKBPA451268
        Drug Product Database2241109
        RxListhttp://www.rxlist.com/cgi/generic/rofecox.htm
        Drugs.comhttp://www.drugs.com/mtm/rofecoxib.html
        WikipediaRofecoxib
        ATC CodesM01AH02
        AHFS CodesNot Available
        PDB EntriesNot Available
        FDA labelshow(291 KB)
        MSDSNot Available
        Interactions
        Drug Interactions
        Drug
        AminophyllineRofecoxib increases the effect and toxicity of theophylline
        LithiumThe COX-2 inhibitor increases serum levels of lithium
        MethotrexateRofecoxib increases the levels of methotrexate
        OxtriphyllineRofecoxib increases the effect and toxicity of theophylline
        TheophyllineRofecoxib increases the effect and toxicity of theophylline
        Food InteractionsNot Available

        1. Prostaglandin G/H synthase 2

        Kind: protein

        Organism: Human

        Pharmacological action: yes

        Actions: inhibitor

        Components

        Name UniProt ID Details
        Prostaglandin G/H synthase 2 P35354 Details

        References:

        1. Ehrich EW, Schnitzer TJ, McIlwain H, Levy R, Wolfe F, Weisman M, Zeng Q, Morrison B, Bolognese J, Seidenberg B, Gertz BJ: Effect of specific COX-2 inhibition in osteoarthritis of the knee: a 6 week double blind, placebo controlled pilot study of rofecoxib. Rofecoxib Osteoarthritis Pilot Study Group. J Rheumatol. 1999 Nov;26(11):2438-47. Pubmed
        2. Malmstrom K, Daniels S, Kotey P, Seidenberg BC, Desjardins PJ: Comparison of rofecoxib and celecoxib, two cyclooxygenase-2 inhibitors, in postoperative dental pain: a randomized, placebo- and active-comparator-controlled clinical trial. Clin Ther. 1999 Oct;21(10):1653-63. Pubmed
        3. Langman MJ, Jensen DM, Watson DJ, Harper SE, Zhao PL, Quan H, Bolognese JA, Simon TJ: Adverse upper gastrointestinal effects of rofecoxib compared with NSAIDs. JAMA. 1999 Nov 24;282(20):1929-33. Pubmed
        4. Pascucci RA: COX-2-specific inhibition: implications for clinical practice. J Am Osteopath Assoc. 1999 Nov;99(11 Suppl):S18-22. Pubmed
        5. Hawkey C, Laine L, Simon T, Beaulieu A, Maldonado-Cocco J, Acevedo E, Shahane A, Quan H, Bolognese J, Mortensen E: Comparison of the effect of rofecoxib (a cyclooxygenase 2 inhibitor), ibuprofen, and placebo on the gastroduodenal mucosa of patients with osteoarthritis: a randomized, double-blind, placebo-controlled trial. The Rofecoxib Osteoarthritis Endoscopy Multinational Study Group. Arthritis Rheum. 2000 Feb;43(2):370-7. Pubmed
        6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
        7. Ashok V, Dash C, Rohan TE, Sprafka JM, Terry PD: Selective cyclooxygenase-2 (COX-2) inhibitors and breast cancer risk. Breast. 2010 Aug 17. Pubmed
        8. Baron JA, Sandler RS, Bresalier RS, Lanas A, Morton DG, Riddell R, Iverson ER, Demets DL: Cardiovascular events associated with rofecoxib: final analysis of the APPROVe trial. Lancet. 2008 Nov 15;372(9651):1756-64. Epub 2008 Oct 14. Pubmed
        9. Chakraborti AK, Garg SK, Kumar R, Motiwala HF, Jadhavar PS: Progress in COX-2 inhibitors: a journey so far. Curr Med Chem. 2010;17(15):1563-93. Pubmed
        10. Matheson AJ, Figgitt DP: Rofecoxib: a review of its use in the management of osteoarthritis, acute pain and rheumatoid arthritis. Drugs. 2001;61(6):833-65. Pubmed

        2. Elastin

        Kind: protein

        Organism: Human

        Pharmacological action: unknown

        Actions: other/unknown

        Components

        Name UniProt ID Details
        Elastin P15502 Details

        References:

        1. Oitate M, Hirota T, Koyama K, Inoue S, Kawai K, Ikeda T: Covalent binding of radioactivity from [14C]rofecoxib, but not [14C]celecoxib or [14C]CS-706, to the arterial elastin of rats. Drug Metab Dispos. 2006 Aug;34(8):1417-22. Epub 2006 May 5. Pubmed
        2. Oitate M, Hirota T, Takahashi M, Murai T, Miura S, Senoo A, Hosokawa T, Oonishi T, Ikeda T: Mechanism for covalent binding of rofecoxib to elastin of rat aorta. J Pharmacol Exp Ther. 2007 Mar;320(3):1195-203. Epub 2006 Dec 12. Pubmed
        3. Oitate M, Hirota T, Murai T, Miura S, Ikeda T: Covalent binding of rofecoxib, but not other cyclooxygenase-2 inhibitors, to allysine aldehyde in elastin of human aorta. Drug Metab Dispos. 2007 Oct;35(10):1846-52. Epub 2007 Jul 9. Pubmed

        1. Cytochrome P450 1A2

        Kind: protein

        Organism: Human

        Pharmacological action: unknown

        Actions: substrate inhibitor

        Components

        Name UniProt ID Details
        Cytochrome P450 1A2 P05177 Details

        References:

        1. Wang B, Zhou SF: Synthetic and natural compounds that interact with human cytochrome P450 1A2 and implications in drug development. Curr Med Chem. 2009;16(31):4066-218. Pubmed
        2. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. Pubmed
        3. 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

        2. Cytochrome P450 3A4

        Kind: protein

        Organism: Human

        Pharmacological action: unknown

        Actions: substrate inducer

        Components

        Name UniProt ID Details
        Cytochrome P450 3A4 P08684 Details

        References:

        1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. Pubmed
        2. 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

        3. Prostaglandin G/H synthase 1

        Kind: protein

        Organism: Human

        Pharmacological action: unknown

        Actions: substrate

        Components

        Name UniProt ID Details
        Prostaglandin G/H synthase 1 P23219 Details

        References:

        1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. Pubmed

        4. 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

        5. Cytochrome P450 2C9

        Kind: protein

        Organism: Human

        Pharmacological action: unknown

        Actions: substrate

        Components

        Name UniProt ID Details
        Cytochrome P450 2C9 P11712 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

        1. Multidrug resistance-associated protein 4

        Kind: protein

        Organism: Human

        Pharmacological action: unknown

        Actions: inhibitor

        Components

        Name UniProt ID Details
        Multidrug resistance-associated protein 4 O15439 Details

        References:

        1. Reid G, Wielinga P, Zelcer N, van der Heijden I, Kuil A, de Haas M, Wijnholds J, Borst P: The human multidrug resistance protein MRP4 functions as a prostaglandin efflux transporter and is inhibited by nonsteroidal antiinflammatory drugs. Proc Natl Acad Sci U S A. 2003 Aug 5;100(16):9244-9. Epub 2003 Jun 30. Pubmed

        Comments
        Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:11