Flunoxaprofen
Encyclopedia
Flunoxaprofen, also known as Priaxim, is a chiral non-steroidal anti-inflammatory drug
. It is closely related to Naproxen
, which is also an NSAID. Flunoxaprofen has been shown to significantly improve the symptoms of osteoarthritis
and rheumatoid arthritis
. The clinical use of flunoxaprofen has ceased due to concerns of potential hepatotoxicity
.
. It is a two-ring heterocyclic compound containing benzoxazole
.
Because flunoxaprofen has limited water-solubility, additional steps must be taken in order to prepare syrups, creams, suppositories, etc. In order to make flunoxaprofen water-soluble, yet still active and efficient, it must be mixed with lysine
and then suspended in an organic solvent that is soluble in water. A salt will crystallize upon cooling. The salt must then be filtered out and dried. Pharmacological testing of this now water-soluble compound has shown that it has anti-inflammatory properties equal to flunoxaprofen by itself.
in rheumatoid arthritis
patients to show that the two drugs have equivalent therapeutical effects. Both drugs significantly relieve spontaneous pain which occurs both during the day and at night. Both drugs also significantly relive the pain associated with active and passive motion and aid in relieving morning stiffness. The study also showed both drugs to be equally effective at improving grip strength
.
Flunoxaprofen has two enantiomers. The absorption and siposition of both enantiomers were studied in 1988. No significnat differences were seen between the absorption and elimination half-lives between the two. However, further studies have shown that the S-enantiomer is the active form of the drug. Flunoxaprofen is pharmacologically activated through biotransformation of the R-enantiomer to the S-enantiomer. This highly stereoselective chiral inversion is mediated by the FLX-S-Acyl-CoA thioester.
Pharmacokinetic studies have been carried out by determining the level of propranolol enantiomers in the plasma after administering the racemic drug orally. It has been shown that the dextrorotatory form is particularly active and has a much higher therapeutic index
than some other anti-inflammatories, including indomethacin and diclofenac
.
It has also been shown that flunoxaprofen inhibits leukotriene
rather than prostaglandin
synthesis. This is similar to benoxaprofen
. Flunoxaprofen and benoxaprofen
have been shown to have similar absorption characteristics. However, the distribution and elimination of flunoxaprofen has been shown to be much faster than benoxaprofen
.
. The two drugs are carboxylic acid analogs that form reactive acyl glucurnonides. Benoxaprofen
has been shown to be involved in rare hepatotoxicity. Because of this, benoxaprofen
has been removed from the market. In response to this the clinical use of flunoxaprofen has also stopped, even though studies have shown that flunoxaprofen is less toxic than benoxaprofen
.
The toxicity of these nonsteroidal antiinflammatory drugs may be related to the covalent modification of proteins in response to the drugs' reactive acyl glucuronides. The reactivity of the acyl glucoronides can effect the protein binding.
Non-steroidal anti-inflammatory drug
Nonsteroidal anti-inflammatory drugs, usually abbreviated to NSAIDs or NAIDs, but also referred to as nonsteroidal anti-inflammatory agents/analgesics or nonsteroidal Anti-inflammatory medicines , are drugs with analgesic and antipyretic effects and which have, in higher doses, anti-inflammatory...
. It is closely related to Naproxen
Naproxen
Naproxen sodium is a nonsteroidal anti-inflammatory drug commonly used for the reduction of pain, fever, inflammation and stiffness caused by conditions such as:...
, which is also an NSAID. Flunoxaprofen has been shown to significantly improve the symptoms of osteoarthritis
Osteoarthritis
Osteoarthritis also known as degenerative arthritis or degenerative joint disease, is a group of mechanical abnormalities involving degradation of joints, including articular cartilage and subchondral bone. Symptoms may include joint pain, tenderness, stiffness, locking, and sometimes an effusion...
and rheumatoid arthritis
Rheumatoid arthritis
Rheumatoid arthritis is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints. The process produces an inflammatory response of the synovium secondary to hyperplasia of synovial cells, excess synovial fluid, and the development...
. The clinical use of flunoxaprofen has ceased due to concerns of potential hepatotoxicity
Hepatotoxicity
Hepatotoxicity implies chemical-driven liver damage.The liver plays a central role in transforming and clearing chemicals and is susceptible to the toxicity from these agents. Certain medicinal agents, when taken in overdoses and sometimes even when introduced within therapeutic ranges, may injure...
.
Structure
Flunoxaprofen is a derivative of propionic acidPropionic acid
Propanoic acid is a naturally occurring carboxylic acid with chemical formula CH3CH2COOH. It is a clear liquid with a pungent odor...
. It is a two-ring heterocyclic compound containing benzoxazole
Benzoxazole
Benzoxazole is an aromatic organic compound with a molecular formula C7H5NO, a benzene-fused oxazole ring structure, and an odor similar to pyridine. Benzoxazole is used primarily in industry and research, and has no household use....
.
Synthesis and preparation
Synthesis of flunoxaprofen can be seen here
Because flunoxaprofen has limited water-solubility, additional steps must be taken in order to prepare syrups, creams, suppositories, etc. In order to make flunoxaprofen water-soluble, yet still active and efficient, it must be mixed with lysine
Lysine
Lysine is an α-amino acid with the chemical formula HO2CCH4NH2. It is an essential amino acid, which means that the human body cannot synthesize it. Its codons are AAA and AAG....
and then suspended in an organic solvent that is soluble in water. A salt will crystallize upon cooling. The salt must then be filtered out and dried. Pharmacological testing of this now water-soluble compound has shown that it has anti-inflammatory properties equal to flunoxaprofen by itself.
Pharmacokinetics
The efficacy and safety of flunoxaprofen has been compared with those of NaproxenNaproxen
Naproxen sodium is a nonsteroidal anti-inflammatory drug commonly used for the reduction of pain, fever, inflammation and stiffness caused by conditions such as:...
in rheumatoid arthritis
Rheumatoid arthritis
Rheumatoid arthritis is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints. The process produces an inflammatory response of the synovium secondary to hyperplasia of synovial cells, excess synovial fluid, and the development...
patients to show that the two drugs have equivalent therapeutical effects. Both drugs significantly relieve spontaneous pain which occurs both during the day and at night. Both drugs also significantly relive the pain associated with active and passive motion and aid in relieving morning stiffness. The study also showed both drugs to be equally effective at improving grip strength
Grip strength
Grip strength is the force applied by the hand to pull on or suspend from objects and is a specific part of hand strength. Optimum-sized objects permit the hand to wrap around a cylindrical shape with a diameter from one to three inches. Stair rails are an example of where shape and diameter are...
.
Flunoxaprofen has two enantiomers. The absorption and siposition of both enantiomers were studied in 1988. No significnat differences were seen between the absorption and elimination half-lives between the two. However, further studies have shown that the S-enantiomer is the active form of the drug. Flunoxaprofen is pharmacologically activated through biotransformation of the R-enantiomer to the S-enantiomer. This highly stereoselective chiral inversion is mediated by the FLX-S-Acyl-CoA thioester.
Pharmacokinetic studies have been carried out by determining the level of propranolol enantiomers in the plasma after administering the racemic drug orally. It has been shown that the dextrorotatory form is particularly active and has a much higher therapeutic index
Therapeutic index
The therapeutic index is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes death or toxicity ....
than some other anti-inflammatories, including indomethacin and diclofenac
Diclofenac
Diclofenac is a non-steroidal anti-inflammatory drug taken to reduce inflammation and as an analgesic reducing pain in certain conditions....
.
It has also been shown that flunoxaprofen inhibits leukotriene
Leukotriene
Leukotrienes are fatty signaling molecules. They were first found in leukocytes . One of their roles is to trigger contractions in the smooth muscles lining the trachea; their overproduction is a major cause of inflammation in asthma and allergic rhinitis...
rather than prostaglandin
Prostaglandin
A prostaglandin is any member of a group of lipid compounds that are derived enzymatically from fatty acids and have important functions in the animal body. Every prostaglandin contains 20 carbon atoms, including a 5-carbon ring....
synthesis. This is similar to benoxaprofen
Benoxaprofen
Benoxaprofen is a non-steroidal anti-inflammatory drug. It was marketed by Eli Lilly and Company under the brand name Oraflex in the US and as Opren in Europe. Lilly suspended sales of Oraflex in 1982 after reports from the British government and the U.S. Food and Drug Administration of adverse...
. Flunoxaprofen and benoxaprofen
Benoxaprofen
Benoxaprofen is a non-steroidal anti-inflammatory drug. It was marketed by Eli Lilly and Company under the brand name Oraflex in the US and as Opren in Europe. Lilly suspended sales of Oraflex in 1982 after reports from the British government and the U.S. Food and Drug Administration of adverse...
have been shown to have similar absorption characteristics. However, the distribution and elimination of flunoxaprofen has been shown to be much faster than benoxaprofen
Benoxaprofen
Benoxaprofen is a non-steroidal anti-inflammatory drug. It was marketed by Eli Lilly and Company under the brand name Oraflex in the US and as Opren in Europe. Lilly suspended sales of Oraflex in 1982 after reports from the British government and the U.S. Food and Drug Administration of adverse...
.
Adverse effects
A structural analog of flunoxaprofen is benoxaprofenBenoxaprofen
Benoxaprofen is a non-steroidal anti-inflammatory drug. It was marketed by Eli Lilly and Company under the brand name Oraflex in the US and as Opren in Europe. Lilly suspended sales of Oraflex in 1982 after reports from the British government and the U.S. Food and Drug Administration of adverse...
. The two drugs are carboxylic acid analogs that form reactive acyl glucurnonides. Benoxaprofen
Benoxaprofen
Benoxaprofen is a non-steroidal anti-inflammatory drug. It was marketed by Eli Lilly and Company under the brand name Oraflex in the US and as Opren in Europe. Lilly suspended sales of Oraflex in 1982 after reports from the British government and the U.S. Food and Drug Administration of adverse...
has been shown to be involved in rare hepatotoxicity. Because of this, benoxaprofen
Benoxaprofen
Benoxaprofen is a non-steroidal anti-inflammatory drug. It was marketed by Eli Lilly and Company under the brand name Oraflex in the US and as Opren in Europe. Lilly suspended sales of Oraflex in 1982 after reports from the British government and the U.S. Food and Drug Administration of adverse...
has been removed from the market. In response to this the clinical use of flunoxaprofen has also stopped, even though studies have shown that flunoxaprofen is less toxic than benoxaprofen
Benoxaprofen
Benoxaprofen is a non-steroidal anti-inflammatory drug. It was marketed by Eli Lilly and Company under the brand name Oraflex in the US and as Opren in Europe. Lilly suspended sales of Oraflex in 1982 after reports from the British government and the U.S. Food and Drug Administration of adverse...
.
The toxicity of these nonsteroidal antiinflammatory drugs may be related to the covalent modification of proteins in response to the drugs' reactive acyl glucuronides. The reactivity of the acyl glucoronides can effect the protein binding.