Description
Flurbiprofen synthesis was originally reported in 1974. During a study of the pharmacological
properties of a large number of substituted phenylalkanoic acids, including ibuprofen and ibufenac, the most potent
were found to be substituted 2-(4-biphenyl)propionic acids. Further toxicological and pharmacological studies
indicated that flurbiprofen possessed the most favorable therapeutic profile, so it was selected for further clinical
development. It was not marketed until 1987, when it was introduced as the sodium salt as Ocufen, the first topical
NSAID indicated for ophthalmic use in the United States. The indication for Ocufen is the same as that for
Profenal—that is, to inhibit intraoperative miosis induced by prostaglandins in cataract surgery.
Originator
Froben, Boots,UK ,1977
Definition
ChEBI: Flurbiprofen is a monocarboxylic acid that is a 2-fluoro-[1,1'-biphenyl-4-yl] moiety linked to C-2 of propionic acid. A non-steroidal anti-inflammatory, analgesic and antipyretic, it is used as a pre-operative anti-miotic as well as orally for arthritis or dental pain. It has a role as a non-steroidal anti-inflammatory drug, a non-narcotic analgesic, an antipyretic and an EC 1.14.99.1 (prostaglandin-endoperoxide synthase) inhibitor. It is a fluorobiphenyl and a monocarboxylic acid. It is functionally related to a propionic acid. It derives from a hydride of a biphenyl.
Indications
Flurbiprofen (Ansaid) is indicated for the treatment
of rheumatoid arthritis and osteoarthritis. Its half-life,
longer than that of many of the NSAIDs, allows for
twice daily dosing.The most common adverse effects of
flurbiprofen are similar to those of the other acidic
NSAIDs. Flurbiprofen inhibits both COX isoforms
about equally.
Manufacturing Process
A mixture of 3-acetyl-2-fluorobiphenyl, MP 95°C to 96°C, (73.5 g) [prepared from 4.bromo-3-nitroacetophenone (Oelschlage, Ann., 1961, 641, 81) via-4acetyl-2-nitrobiphenyl, MP 106°C to 108°C (Ullman reaction), 4-acetyl-2aminobiphenyl, MP 124°C to 125°C (reduction), and finally the Schiemann reaction], sulfur (17.4 g) and morpholine (87 ml) was refluxed for 16.5 hr, and then the resulting thiomorpholide was hydrolyzed by refluxing with glacial acetic acid (340 ml) concentrated sulfuric acid (54 ml) and water (78 ml) for 24 hr. The cooled solution was diluted with water, and the precipitated crude 2-fluoro-4-biphenylylacetic acid was collected. (A sample was purified by recrystallization to give MP 143°C to 144.5°C; Found (%): C, 73.2; H, 4.8. C14H11FO2 requires C, 73.1; H, 4.8.)
A sodium carbonate solution of the crude acetic acid was washed with ether and then acidified with hydrochloric acid; the required acid was isolated via an ether extraction and was esterified by refluxing for 6 hr with ethanol (370 ml) and concentrated sulfuric acid (15 ml). Excess alcohol was distilled, the residue diluted with water and the required ester isolated in ether. Distillation finally gave ethyl 2-fluoro-4-biphenylacetate, BP 134°C to 136°C/0.25 mm.
This ester (70g) and diethyl carbonate (250 mg) were stirred at 90°C to 100°C while a solution of sodium ethoxide [from sodium (7.8 g) and ethanol (154 ml)] was added over 1 hr. During addition, ethanol was allowed to distill and after addition distillation was continued until the column heat temperature reached 124°C. After cooling the solution to 90°C, dimethyl sulfate (33 ml) was followed by a further 85 ml of diethyl carbonate. This solution was stirred and refluxed for 1 hr and then, when ice cool, was diluted with water and acetic acid (10 ml). The malonate was isolated in ether and fractionally distilled to yield a fraction boiling at 148°C to 153°C/0.075 mm, identified as the alpha-methyl malonate. This was hydrolyzed by refluxing for 1 hr at 2.5 N sodium hydroxide (350 ml) and alcohol (175 ml), excess alcohol was distilled and the residual suspension of sodium salt was acidified with hydrochloric acidto give a precipitate of the alpha-methyl malonic acid. This was decarboxylated by heating at 180°C to 200°C for 30 minutes and recrystallized from petroleum ether (BP 80°C to 100°C) to give 2-(2-fluoro-4biphenylyl)propionic acid, MP 110°C to 111°C
Brand name
Ansaid (Pharmacia & Upjohn).
Therapeutic Function
Antiinflammatory
General Description
Flurbiprofen (Ansaid, Ocufen, Froben), is another drug inthis class indicated for both acute and long-term managementof RA and OA but with a more complex mechanism ofaction. Unlike the other drugs in this class, it does not undergochiral inversion (i.e., the conversion of the “inactive”[R]-enantiomer to the active, [S]-enantiomer). Similar to aspirinand other salicylates, both flurbiprofen enantiomersblock COX-2 induction as well as inhibiting the nuclearfactor-κB-mediated polymorphonuclear leukocyte apoptosissignaling; therefore, both enantiomers are believed to contributeequally to its overall anti-inflammatory action.
(R)-flurbiprofen is actually a strong clinical candidate forthe treatment of Alzheimer disease, because it has beenshown to reduce Aβ42 production by human cells.
Biological Activity
Potent inhibitor of cyclooxygenase (IC 50 values are 0.1 and 0.4 μ M for inhibition of human COX-1 and COX-2 respectively). Analgesic, anti-inflammatory and antipyretic in vivo . Inhibits tumor cell growth in vitro and in vivo . Also inhibits fibroblast proliferation in vitro .
Pharmacokinetics
Flurbiprofen is well absorbed after oral administration, with peak plasma levels being attained within 1.5 hours. Food
alters the rate of absorption but not the extent of its bioavailability. It is extensively bound to plasma proteins (99%).and has a plasma half-life of 2 to 4 hours. Metabolism is extensive, with 60 to 70% of flurbiprofen and its metabolites
being excreted as sulfate and glucuronide conjugates. Flurbiprofen shows some interesting metabolic patterns, with
40 to 47% as the 4′-hydroxy metabolite, 5% as the 3′,4′-dihydroxy metabolite, 20 to 30% as the 3′-hydroxy-
4′-methoxy metabolite, and the remaining 20 to 25% of the drug being excreted unchanged. None of these
metabolites demonstrates significant anti-inflammatory activity.
Clinical Use
Flurbiprofen is indicated as an oral formulation for the acute or long-term treatment of rheumatoid arthritis and
osteoarthritis and as an ophthalmic solution for the inhibition of intraoperative miosis.
Drug interactions
Potentially hazardous interactions with other drugs
ACE inhibitors and angiotensin-II antagonists:
antagonism of hypotensive effect; increased risk of
nephrotoxicity and hyperkalaemia.
Analgesics: avoid concomitant use with other
NSAIDs or aspirin; avoid concomitant use with
ketorolac (increased side effects and haemorrhage).
Antibacterials: possibly increased risk of convulsions
with quinolones.
Anticoagulants: effects of coumarins and
phenindione enhanced; possibly increased risk of
bleeding with heparin, dabigatran and edoxaban -
avoid long term use with edoxaban.
Antidepressants: increased risk of bleeding with
SSRIs or venlafaxine.
Antidiabetics: effects of sulphonylureas enhanced.
Antiepileptics: possibly enhanced effect of phenytoin.
Antivirals: concentration possibly increased by
ritonavir; increased risk of haematological toxicity
with zidovudine.
Ciclosporin: may potentiate nephrotoxicity.
Cytotoxics: reduced excretion of methotrexate;
increased risk of bleeding with erlotinib.
Diuretics: increased risk of nephrotoxicity;
antagonism of diuretic effect; hyperkalaemia with
potassium-sparing diuretics.
Lithium: excretion reduced (risk of lithium toxicity).
Pentoxifylline: increased risk of bleeding.
Tacrolimus: increased risk of nephrotoxicity
Metabolism
Flurbiprofen is metabolised mainly by hydroxylation (via the
cytochrome P450 isoenzyme CYP2C9) and conjugation
in the liver and excreted in the urine. The rate of urinary
excretion of flurbiprofen and its two major metabolites
([2-(2-fluoro-4′-hydroxy-4-biphenylyl) propionic acid] and
[2-(2-fluoro-3′-hydroxy-4′-methoxy-4-biphenylyl) propionic
acid]) in both free and conjugated states is similar for both
the oral and rectal routes of administration.
