Loxoprofen is an anti-inflammatory prodrug (NSAID) and a non-selective COX inhibitor with IC50 values of 6.5 and 13.5 μM for COX-1 and COX-2, respectively, in human whole blood assays [1]. Loxoprofen (LOX) is a non-selective cyclooxygenase inhibitor frequently used to research pain and inflammation in chronic and transitory disorders. Its alcohol metabolite is produced by carbonyl reductase (CR) and comprises of active trans-LOX and inactive cis-LOX. In addition, LOX can also be transformed into inactive hydroxylated metabolites (OH-LOXs) by cytochrome P450 (CYP) [2].

By lowering inflammation, loxoprofen sodium (4 mg/kg/day; PO; 1 or 8 weeks) lowers atherosclerosis in mice [3]. By blocking VEGF, loxoprofen sodium (60 μg/mL; oral; 24 days) prevents tumor growth in mice [4].

Animal/Disease Models: ApoE-/- mice (C57BL/6J-Apoetm1Unc), 8 to 16 weeks old, high-fat diet (0.2% cholesterol, 21% saturated fat) [3]
Doses: 4 mg/kg/day, given in drinking water Medication method: Oral administration at 8 to 16 weeks of age or 15 to 16 weeks of age.
Experimental Results: Inhibition of platelet thromboxane production and platelet aggregation. Reduce the extent of atherosclerosis. Inhibits the production of PGE2, TxB2 and PGI2.

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Animal/Disease Models: 6weeks old male C57BL/6 and BDF1 mice, 100 μL suspension of LLC cells and KLN205 cells (2×106 cells/mL) were subcutaneously (sc) (sc) injected into C57BL/6 and BDF1 mice respectively [4].
Doses: 60 μg/mL
Route of Administration: Orally administered daily for 24 days
Experimental Results: Inhibited tumor growth and angiogenesis in LLC tumor mice, inhibited VEGF expression, and inhibited HUVEC tube formation.

Absorption, Distribution and Excretion
Loxoprofen is rapidly and completely absorbed from the gastrointestinal tract, with a bioavailability of 95%. The absorption period occurs within 4-6 hours after administration. Taking it with food slightly reduces the absorption rate. 50% is excreted by the kidneys. 20-30% is excreted in feces. The volume of distribution of loxoprofen is 0.16 L/kg. Most of the drug exists as unchanged loxoprofen, 6-O-demethylloxoprofen (less than 1%), and glucuronide or other conjugates (66-92%). Metabolites may accumulate in patients with renal failure. Metabolism/Metabolites Loxoprofen is a prodrug that is rapidly converted in the liver by carbonyl reductase to its active trans-alcohol metabolite. This process also produces a cis-alcohol metabolite, but this isomer has almost no pharmacological activity. The parent drug can also be oxidized by CYP3A4/5 to generate two hydroxylated metabolites (M3 and M4), and glucuronidated by UGT2B7 to generate two glucuronide metabolites (M5 and M6). The alcohol metabolites of loxoprofen also undergo glucuronidation by UGT2B7 before excretion, generating two glucuronide metabolites (M7 and M8). When applied topically, loxoprofen is metabolized in the skin by carbonyl reductase to the active trans-alcohol form.
Biological Half-Life
The elimination half-life of loxoprofen is approximately 15 hours. Stable concentrations are reached after 2-3 doses.

Protein Binding
99% of loxoprofen is bound to albumin. When the dose of loxoprofen exceeds 500 mg/day, drug clearance increases due to plasma protein saturation.

[1]. Evaluation of loxoprofen and its alcohol metabolites for potency and selectivity of inhibition of cyclooxygenase-2. Bioorg Med Chem Lett. 2004;14(5):1201-1203.

[2]. Assessing Drug Interaction and Pharmacokinetics of Loxoprofen in Mice Treated with CYP3A Modulators. Pharmaceutics. 2019;11(9):479. Published 2019 Sep 16.

[3]. Loxoprofen Sodium, a Non-Selective NSAID, Reduces Atherosclerosis in Mice by Reducing Inflammation. J Clin Biochem Nutr. 2010 Sep;47(2):138-47.

[4]. Loxoprofen sodium suppresses mouse tumor growth by inhibiting vascular endothelial growth factor. Acta Oncol. 2003;42(1):62-70.

Loxoprofen is a monocarboxylic acid, a derivative of propionic acid, in which a hydrogen atom at the 2-position is replaced by a 4-[(2-oxocyclopentyl)methyl]phenyl group. It is a prodrug that is rapidly converted to its active trans-alcohol metabolite after oral administration. Loxoprofen possesses various pharmacological effects, including nonsteroidal anti-inflammatory drug (NSAID), non-narcotic analgesic, antipyretic, EC 1.14.99.1 (prostaglandin intraperoxide synthase) inhibitor, and prodrug activity. It is a monocarboxylic acid belonging to the cyclopentanone class of compounds. Its function is related to propionic acid. It is the conjugate acid of loxoprofen (1-). Loxoprofen is a propionic acid derivative NSAID. In Brazil, Mexico, and Japan, it is marketed by Sankyo Co., Ltd. under the brand name Loxonin; in India, it is marketed under the brand name Loxomac; and in Argentina, it is marketed under the brand name Oxeno. A transdermal formulation was approved for marketing in Japan in January 2006.

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Drug Indications
Loxoprofen is a nonsteroidal anti-inflammatory drug (NSAID) indicated for the treatment of pain and inflammation caused by musculoskeletal and joint disorders. In addition to its analgesic effect, it also has antipyretic and anti-inflammatory properties.Mechanism of Action
Loxoprofen itself is a prodrug with virtually no pharmacological activity—it is rapidly metabolized to its trans-alcohol form, which is a potent nonselective cyclooxygenase inhibitor. Cyclooxygenase (COX) exists in two forms, COX-1 and COX-2, each performing different functions. COX-1 is present in human cells and is continuously released, performing cellular maintenance functions such as mucus production and platelet aggregation. COX-2 is induced to be expressed after human cell damage or other stimuli and appears in large quantities at the site of damage/irritation, ultimately mediating inflammation and pain.
Loxoprofen's active metabolites inhibit two COX isoenzymes, thereby reducing the expression of various pain, inflammation, and fever mediators, such as prostaglandins, prostacyclin, and thromboxane.

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Pharmacodynamics
Loxoprofen is a non-selective cyclooxygenase inhibitor. Cyclooxygenases are responsible for generating various biologically active pain, fever, and inflammation mediators. These mediators include prostaglandins, prostacyclin, thromboxane, and arachidonic acid.

C15H18O3

246.3016

246.125

68767-14-6

Loxoprofen sodium;80382-23-6;Loxoprofen sodium (dihydrate);226721-96-6;Loxoprofen-d4

3965

White to off-white solid powder

1.2±0.1 g/cm3

417.9±20.0 °C at 760 mmHg

108.5 - 111ºC

220.7±18.3 °C

0.0±1.0 mmHg at 25°C

1.568

1.87

1

3

4

18

316

0

YMBXTVYHTMGZDW-UHFFFAOYSA-N

InChI=1S/C15H18O3/c1-10(15(17)18)12-7-5-11(6-8-12)9-13-3-2-4-14(13)16/h5-8,10,13H,2-4,9H2,1H3,(H,17,18)

2-[4-[(2-oxocyclopentyl)methyl]phenyl]propanoic acid

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ≥ 100 mg/mL (~406.01 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (10.15 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (10.15 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (10.15 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)