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药品详细

Rofecoxib (罗非昔布 )

化学结构式图
中文名
罗非昔布
英文名
Rofecoxib
分子式
Not Available
化学名
4-(4-methanesulfonylphenyl)-3-phenyl-2,5-dihydrofuran-2-one
分子量
Average: 314.356
Monoisotopic: 314.061279626
CAS号
162011-90-7
ATC分类
M01A 未知
药物类型
small molecule
阶段
商品名
Vioxx;
同义名
MK 966;MK 996;rofecoxib;
基本介绍

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.

生产厂家
  • Merck research laboratories div merck co inc
封装厂家
参考
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
剂型
Form Route Strength
Suspension Oral
Tablet Oral
规格
化合物类型
Type small molecule
Classes Not Available
Substructures Not Available
适应症
ANTIINFLAMMATORY AND ANTIRHEUMATIC 消炎抗风湿;
药理
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.

Enzyme Metabolite Reaction Km Vmax
Prostaglandin G/H synthase 1 Dihydro-5-Hydroxyrofecoxib
Prostaglandin G/H synthase 1 Rofecoxib-threo-3,4-dihydrohydroxy acid reduction
Prostaglandin G/H synthase 1 Rofecoxib-erythro-3,4-dihydrohydroxy acid reduction
Cytochrome P450 1A2 5-Hydroxyrofecoxib oxidation
Cytochrome P450 3A4 5-Hydroxyrofecoxib oxidation
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
理化性质
Properties
State solid
Melting point Not Available
Experimental Properties
Property Value Source
water solubility Insoluble PhysProp
logP 3.2 PhysProp
Predicted Properties
Property Value Source
water solubility 1.06e-02 g/l ALOGPS
logP 2.32 ALOGPS
logP 2.56 ChemAxon Molconvert
logS -4.47 ALOGPS
pKa 19.70 ChemAxon Molconvert
hydrogen acceptor count 3 ChemAxon Molconvert
hydrogen donor count 0 ChemAxon Molconvert
polar surface area 60.44 ChemAxon Molconvert
rotatable bond count 3 ChemAxon Molconvert
refractivity 84.08 ChemAxon Molconvert
polarizability 31.74 ChemAxon Molconvert
药物相互作用
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
食物相互作用
Not Available

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