Banner
Identification
Name Rofecoxib
Accession Number DB00533 (APRD00151)
Type small molecule
Groups withdrawn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
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
MK 966
MK 996
Salts Not Available
Brand names
Name Company
Vioxx
Brand mixtures Not Available
Categories
  • Cyclooxygenase Inhibitors
  • Cyclooxygenase 2 Inhibitors
CAS number 162011-90-7
Weight Average: 314.356
Monoisotopic: 314.061279626
Chemical Formula C17H14O4S
InChI Key InChIKey=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
Plain Text
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
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Not Available
Classes Not Available
Substructures Not Available
Pharmacology
Indication For 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.
Pharmacodynamics Rofecoxib, 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 action The 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.
Absorption The mean oral bioavailability of rofecoxib at therapeutically recommended doses of 12.5, 25, and 50 mg is approximately 93%.
Volume of distribution Not Available
Protein binding 87%
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.

Important The metabolism module of DrugBank is currently in beta. Questions or suggestions? Please contact us.

Substrate Enzymes Product
Rofecoxib
5-Hydroxyrofecoxib Details
Rofecoxib
Dihydro-5-Hydroxyrofecoxib Details
Rofecoxib
Rofecoxib-threo-3,4-dihydrohydroxy acid Details
Rofecoxib
Rofecoxib-erythro-3,4-dihydrohydroxy acid Details
Route of elimination Not Available
Half life 17 hours
Clearance Not Available
Toxicity No 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
Pathway Name SMPDB ID
Smp00087 Rofecoxib Pathway SMP00087
Pharmacoeconomics
Manufacturers
  • Merck research laboratories div merck co inc
Packagers
Dosage forms
Form Route Strength
Suspension Oral
Tablet Oral
Prices Not Available
Patents
Country Patent Number Approved Expires (estimated)
United States 6063811 1997-11-06 2017-11-06
United States 5474995 1993-06-24 2013-06-24
Properties
State solid
Experimental Properties
Property Value Source
water solubility Insoluble Not Available
logP 3.2 Not Available
Predicted Properties
Property Value Source
water solubility 1.06e-02 g/l ALOGPS
logP 2.32 ALOGPS
logP 2.56 ChemAxon
logS -4.5 ALOGPS
pKa (strongest acidic) 14.84 ChemAxon
pKa (strongest basic) -7 ChemAxon
physiological charge 0 ChemAxon
hydrogen acceptor count 3 ChemAxon
hydrogen donor count 0 ChemAxon
polar surface area 60.44 ChemAxon
rotatable bond count 3 ChemAxon
refractivity 84.08 ChemAxon
polarizability 31.74 ChemAxon
References
Synthesis Reference Not 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
Resource Link
KEGG Drug D00568 Link_out
KEGG Compound C07590 Link_out
PubChem Compound 5090 Link_out
PubChem Substance 46504787 Link_out
ChemSpider 4911 Link_out
BindingDB 22369 Link_out
ChEBI 8887 Link_out
ChEMBL 8887 Link_out
Therapeutic Targets Database DAP001338 Link_out
PharmGKB PA451268 Link_out
Drug Product Database 2241109 Link_out
RxList http://www.rxlist.com/cgi/generic/rofecox.htm Link_out
Drugs.com http://www.drugs.com/mtm/rofecoxib.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Rofecoxib Link_out
ATC Codes
  • M01AH02
AHFS Codes Not Available
PDB Entries Not Available
FDA label show (291 KB)
MSDS Not Available
Interactions
Drug Interactions
Drug Interaction
Aminophylline Rofecoxib increases the effect and toxicity of theophylline
Lithium The COX-2 inhibitor increases serum levels of lithium
Methotrexate Rofecoxib increases the levels of methotrexate
Oxtriphylline Rofecoxib increases the effect and toxicity of theophylline
Theophylline Rofecoxib increases the effect and toxicity of theophylline
Food Interactions Not Available
Targets

1. Prostaglandin G/H synthase 2

Pharmacological action: yes
Actions: inhibitor

May have a role as a major mediator of inflammation and/or a role for prostanoid signaling in activity-dependent plasticity

Organism class: human
UniProt ID: P35354 Link_out
Gene: PTGS2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Pharmacological action: unknown
Actions: other/unknown

Major structural protein of tissues such as aorta and nuchal ligament, which must expand rapidly and recover completely. Molecular determinant of the late arterial morphogenesis, stabilizing arterial structure by regulating proliferation and organization of vascular smooth muscle

Organism class: human
UniProt ID: P15502 Link_out
Gene: ELN Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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
Enzymes

1. Cytochrome P450 1A2

Actions: substrate, inhibitor

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 unrelated compounds, including steroids, fatty acids, and xenobiotics. Most active in catalyzing 2-hydroxylation. Caffeine is metabolized primarily by cytochrome CYP1A2 in the liver through an initial N3-demethylation. Also acts in the metabolism of aflatoxin B1 and acetaminophen

UniProt ID: P05177 Link_out
Gene: CYP1A2
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: substrate, inducer

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4- hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. The enzyme also hydroxylates etoposide

UniProt ID: P08684 Link_out
Gene: CYP3A4
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: substrate

May play an important role in regulating or promoting cell proliferation in some normal and neoplastically transformed cells

UniProt ID: P23219 Link_out
Gene: PTGS1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: substrate

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 unrelated compounds, including steroids, fatty acids, and xenobiotics. In the epoxidation of arachidonic acid it generates only 14,15- and 11,12-cis-epoxyeicosatrienoic acids. It is the principal enzyme responsible for the metabolism the anti- cancer drug paclitaxel (taxol)

UniProt ID: P10632 Link_out
Gene: CYP2C8
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: substrate

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 unrelated compounds, including steroids, fatty acids, and xenobiotics. This enzyme contributes to the wide pharmacokinetics variability of the metabolism of drugs such as S- warfarin, diclofenac, phenytoin, tolbutamide and losartan

UniProt ID: P11712 Link_out
Gene: CYP2C9
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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
Transporters

1. Multidrug resistance-associated protein 4

Actions: inhibitor

May be an organic anion pump relevant to cellular detoxification

UniProt ID: O15439 Link_out
Gene: ABCC4 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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 February 08, 2013 16:19