Ketoprofen

Ketoprofen is one of the propionic acid class of nonsteroidal anti-inflammatory drugs (NSAID) with analgesic and antipyretic effects.[1] It acts by inhibiting the body's production of prostaglandin.

Ketoprofen
Clinical data
Trade namesOruvail, others
AHFS/Drugs.comMonograph
MedlinePlusa686014
License data
Pregnancy
category
  • AU: C
Routes of
administration		By mouth, topical, intravenous (veterinary use)
ATC code
Legal status
Legal status
  • AU: S3 (Pharmacist only) / S4
  • US: ℞-only
  • Rx-only & OTC
Pharmacokinetic data
Protein binding99%
Elimination half-life2–2.5 hours
Identifiers
IUPAC name
  • (RS)-2-(3-benzoylphenyl)propanoic acid
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.040.676
Chemical and physical data
FormulaC16H14O3
Molar mass254.285 g·mol−1
3D model (JSmol)
ChiralityRacemic mixture
SMILES
  • CC(c1cccc(c1)C(=O)c2ccccc2)C(=O)O
InChI
  • InChI=1S/C16H14O3/c1-11(16(18)19)13-8-5-9-14(10-13)15(17)12-6-3-2-4-7-12/h2-11H,1H3,(H,18,19) Y
  • Key:DKYWVDODHFEZIM-UHFFFAOYSA-N Y
 NY (what is this?)  (verify)

It was patented in 1967 and approved for medical use in 1980.[2]

Medical uses

Ketoprofen is generally prescribed for arthritis-related inflammatory pains or severe toothaches that result in the inflammation of the gums.

Ketoprofen topical patches are being used for treatment of musculoskeletal pain.[3][4][5]

Ketoprofen can also be used for treatment of some pain, especially nerve pain such as sciatica, postherpetic neuralgia and referred pain for radiculopathy, in the form of a cream, ointment, liquid, spray, or gel, which may also contain ketamine and lidocaine, along with other agents which may be useful, such as cyclobenzaprine, amitriptyline, acyclovir, gabapentin, orphenadrine and other drugs used as NSAIDs or adjuvant, atypical or potentiators for pain treatment.

Trial is been going on for using this drug along with ibuprofen for management of lymphedema . Animal trial and some human trials has been shown significant improvement over placebo control. Dr Stanley G Rockson, of Stanford University is leading these researches.

Efficacy

A 2013 systematic review indicated "The efficacy of orally administered ketoprofen in relieving moderate-severe pain and improving functional status and general condition was significantly better than that of ibuprofen and/or diclofenac."[6] A 2017 Cochrane systematic review investigating ketoprofen as a single-dose by mouth in acute, moderate-to-severe postoperative pain concluded that its efficacy is equivalent to drugs such as ibuprofen and diclofenac.[7]

There is evidence supporting topical ketoprofen for osteoarthritis but not other chronic musculoskeletal pain.[8]

Adverse effects

In October 2020, the U.S. Food and Drug Administration (FDA) required the drug label to be updated for all nonsteroidal anti-inflammatory medications to describe the risk of kidney problems in fetuses that result in low amniotic fluid.[9][10] They recommend avoiding NSAIDs in pregnant women at 20 weeks or later in pregnancy.[9][10]

Mechanism

Ketoprofen undergoes metabolism in the liver via conjugation with glucuronic acid (glucuronidation) by UGT enzymes, hydroxylation of the benzoyl ring by the CYP3A4 and CYP2C9 enzymes, and reduction of its ketone moiety (a carbonyl functional group, i.e. with carbon-oxygen double bond)[11] by carbonyl reducing enzymes (CREs).[12][13] Ketoprofen is used for its antipyretic, analgesic, and anti-inflammatory properties by inhibiting cyclooxygenase-1 and -2 (COX-1 and COX-2) enzymes reversibly, which decreases production of proinflammatory prostaglandin precursors.[12][14]

The patches have been shown to provide rapid and sustained delivery to underlying tissues without significantly increasing levels of drug concentration in the blood when compared to the traditional oral administration.[5][15]

Chirality and biological activity

Ketoprofen has one stereogenic center in the side chain and hence exists as mirror-image twins. Majority of the profens are marketed as racemic mixtures. For most of the NSAIDs the pharmacological activity reside in the (S)-enantiomers with their (R)-enantiomer of virtually inactive. An interesting observation about most profens including ketoprofen is that they undergo unidirectional metabolic inversion, chiral inversion, of the (R)- acid to its (S)-mirror-image version with no other change in the molecule.[16][17][18]

Available forms

Ketoprofen was available over-the-counter in the United States in the form of 12.5 mg coated tablets (Orudis KT and Actron), but this form has been discontinued. It is available by prescription capsules.

Ketoprofen is also available as a 2.5% gel for topical application, and it is also available as a patch for topical analgesia and anti-inflammatory action. However, the gel is not sold in the United States.

Brand names in Australia are Orudis and Oruvail. It is available in Japan in a transdermal patch Mohrus Tape, made by Hisamitsu Pharmaceutical. It is available in the UK as Ketoflam and Oruvail, in Ireland as Fastum Gel, in Estonia as Keto, Ketonal, and Fastum Gel, in Finland as Ketorin, Keto, Ketomex, and Orudis; in France as Profénid, Bi-Profénid and Ketum; in Italy as Ketodol, Fastum Gel, Lasonil, Orudis and Oki; in Poland as Ketonal, Ketonal active, Ketolek, in Serbia, Slovenia and Croatia as Knavon and Ketonal; in Romania as Ketonal and Fastum Gel; in Mexico as Arthril; in Norway as Zon and Orudis; in Russia as ОКИ (OKI), Fastum Gel and Ketonal; in Spain as Actron and Fastum Gel; in Albania as Oki and Fastum Gel and in Venezuela as Ketoprofeno as an injectable solution of 100 mg and 150 mg capsules.

In some countries, the optically pure (S)-enantiomer (dexketoprofen) is available; its trometamol salt is said to be particularly rapidly reabsorbed from the gastrointestinal tract, having a rapid onset of effects.

The earliest report of therapeutic use in humans was in 1972.[19]

Veterinary medicine

Ketoprofen is a common NSAID, antipyretic, and analgesic used in horses and other equines.[20] It is most commonly used for musculoskeletal pain, joint problems, and soft tissue injury, as well as laminitis. It is also used to control fevers and prevent endotoxemia. It is also used as a mild painkiller in smaller animals, generally following surgical procedures.

In horses, it is given at a dose of 2.2 mg/kg/day. Studies have shown that it does not inhibit 5-lipoxygenase and leukotriene B4,[21] as originally claimed.[22] It is therefore not considered superior to phenylbutazone as previously believed, although clinical signs of lameness are reduced with its use.[23] In fact, phenylbutazone was shown superior to ketoprofen in cases of experimentally-induced synovitis when both drugs were used at labeled dosages.[24]

Administration

Ketoprofen, when administered intravenously, is recommended for a maximum of five days of use. Its analgesic and antipyretic effects begin to occur one to two hours following administration. The most common dosage is 1 mg/ lb, once per day, although this dosage may be lowered for ponies, which are most susceptible to NSAID side effects. It is also available as a capsule dosage form and tablet.

Ecological problems

Experiments have found ketoprofen, like diclofenac, is a veterinary drug causing lethal effects in red-headed vultures. Vultures feeding on the carcasses of recently treated livestock develop acute kidney failure within days of exposure.[25]

References
  1. Kantor, T. G. (1986). "Ketoprofen: a review of its pharmacologic and clinical properties". Pharmacotherapy. 6 (3): 93–103. doi:10.1002/j.1875-9114.1986.tb03459.x. PMID 3526298. S2CID 25309841.
  2. Fischer, Jnos; Ganellin, C. Robin (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 520. ISBN 9783527607495.
  3. Mazières, B; Rouanet, S; Guillon, Y; Scarsi, C; Reiner, V (2005). "Topical ketoprofen patch in the treatment of tendinitis: a randomized, double blind, placebo controlled study". The Journal of Rheumatology. 32 (8): 1563–70. PMID 16078335.
  4. Mazières, B (2005). "Topical ketoprofen patch". Drugs in R&D. 6 (6): 337–44. doi:10.2165/00126839-200506060-00003. PMID 16274258. S2CID 30719197.
  5. Sekiya, I; Morito, T; Hara, K; Yamazaki, J; Ju, YJ; Yagishita, K; Mochizuki, T; Tsuji, K; Muneta, T (2010). "Ketoprofen Absorption by Muscle and Tendon after Topical or Oral Administration in Patients Undergoing Anterior Cruciate Ligament Reconstruction". AAPS PharmSciTech. 11 (1): 154–58. doi:10.1208/s12249-009-9367-2. PMC 2850498. PMID 20087696.
  6. Sarzi-Puttini, P; Atzeni, F; Lanata, L; Bagnasco, M (2013). "Efficacy of ketoprofen vs. ibuprofen and diclofenac: a systematic review of the literature and meta-analysis". Clinical and Experimental Rheumatology. 31 (5): 731–8. PMID 23711416.
  7. Gaskell, Helen; Derry, Sheena; Wiffen, Philip J.; Moore, R. Andrew (2017). "Single dose oral ketoprofen or dexketoprofen for acute postoperative pain in adults". The Cochrane Database of Systematic Reviews. 2019 (5): CD007355. doi:10.1002/14651858.CD007355.pub3. ISSN 1469-493X. PMC 6481461. PMID 28540716.
  8. Derry, S; Conaghan, P; Da Silva, JA; Wiffen, PJ; Moore, RA (22 April 2016). "Topical NSAIDs for chronic musculoskeletal pain in adults" (PDF). The Cochrane Database of Systematic Reviews. 4: CD007400. doi:10.1002/14651858.cd007400.pub3. PMC 6494263. PMID 27103611.
  9. This article incorporates text from this source, which is in the public domain: "FDA Warns that Using a Type of Pain and Fever Medication in Second Half of Pregnancy Could Lead to Complications". U.S. Food and Drug Administration (FDA) (Press release). 15 October 2020. Retrieved 15 October 2020.
  10. This article incorporates text from this source, which is in the public domain: "NSAIDs may cause rare kidney problems in unborn babies". U.S. Food and Drug Administration. 21 July 2017. Retrieved 15 October 2020.
  11. Malátková P, Wsól V (February 2014). "Carbonyl reduction pathways in drug metabolism". Drug Metabolism Reviews. 46 (1): 96–123. doi:10.3109/03602532.2013.853078. PMID 24171394. S2CID 43774709.
  12. Ketoprofen. (n.d.). Millennium Web Catalog. Retrieved February 1, 2010, from http://0-online.lexi.com.library.touro.edu
  13. Lemke TL, Williams DA, Roche VF, Zito SW. Foyes Principles of Medical Chemistry. 6th ed. Philadelphia: Lippincott Williams and Wilkins; 2008.
  14. Ketoprofen. (n.d.). Micromedex. Retrieved February 1, 2010, from https://bb-tuc.touro.edu/webapps/portal/frameset.jsp?tab_id=_102_1
  15. Gayman, MD; Turner, RJ; Cui, M (2008). "Physical Limitations and Depressive Symptoms: Exploring the Nature of the Association". The Journals of Gerontology. Series B, Psychological Sciences and Social Sciences. 63 (4): S219–S228. doi:10.1093/geronb/63.4.s219. PMC 2844725. PMID 18689771.
  16. Hutt, Andrew J; Caldwell, John (2011-04-12). "The metabolic chiral inversion of 2-arylpropionic acids—a novel route with pharmacological consequences". Journal of Pharmacy and Pharmacology. 35 (11): 693–704. doi:10.1111/j.2042-7158.1983.tb02874.x. ISSN 2042-7158. PMID 6139449. S2CID 40669413.
  17. Caldwell, John; Hutt, Andrew J.; Fournel-Gigleux, Sylvie (1988). "The metabolic chiral inversion and dispositional enantioselectivity of the 2-arylpropionic acids and their biological consequences". Biochemical Pharmacology. 37 (1): 105–114. doi:10.1016/0006-2952(88)90762-9. PMID 3276314.
  18. The impact of stereochemistry on drug development and use. Hassan Y. Aboul-Enein, Irving W. Wainer. New York: Wiley. 1997. ISBN 0-471-59644-2. OCLC 35262289.{{cite book}}: CS1 maint: others (link)
  19. A. N. Gyory; M. Bloch; H. C. Burry; R. Grahame (1972). "Orudis in Management of Rheumatoid Arthritis and Osteoarthrosis of the Hip: Comparison with Indomethacin". British Medical Journal. 4 (5837): 398–400. doi:10.1136/bmj.4.5837.398. PMC 1786628. PMID 4564764.
  20. Forney, Barbara C, MS, VMD. Equine Medications, Revised Edition. Blood Horse Publications. Lexington, KY. Copyright 2007.
  21. Salman, JA; Tilling, LC; Monscada, S (1984). "Benoxaprofen does not inhibit formation of leukotriene B4 in a model of acute inflammation". Biochem Pharmacol. 33: 28–2930.
  22. Betley, M; Sutherland, SF; Gregoricka, MJ; Pollett, RA (1991). "The analgesic effect of ketoprofen for use in treating equine colic as compared to flunixin meglumine". Equine Pract. 13: 11–16.
  23. Owens JG, Kamerling SG, Keowen ML. Anti-inflammatory effects and pharmacokinetics of ketoprofen in a model of equine synovitis, in Proceedings. 6th Int Cong Eur Assoc Vet Pharmacol Toxicol 1994;170–171.
  24. Owens JG, Kamerling SG, Stanton SR, et al. Effects of pretreatment with ketoprofen and phenylbutazone on experi- mentally induced synovitis in dogs. 866 – 872.
  25. Naidoo V, Wolter K, Cromarty D, Diekmann M, Duncan N, Meharg AA, Taggart MA, Venter L, Cuthbert R (2009). "Toxicity of non-steroidal anti-inflammatory drugs to Gyps vultures: a new threat from ketoprofen". Biology Letters. 6 (3): 339–341. doi:10.1098/rsbl.2009.0818. ISSN 1744-9561. PMC 2880042. PMID 20007163.
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