Naproxen etemesil is a lipophilic, non-acidic, inactive prodrug of naproxen that, when absorbed, hydrolyzes to produce naproxen that is pharmacologically active. One well-known non-steroidal anti-inflammatory medication is naproxen. With IC50s of 2.2 μg/mL and 1.3 μg/mL, respectively, naproxen is a nearly equal inhibitor of COX-1 and COX-2 in intact cells [1].

Naproxen reduces inflammation and inhibits fibrosis in a mouse model of lung fibrosis caused by bleomycin. Additionally, naproxen inhibits the production of the Smad3/4 complex and TGF-β levels [2]. Similar potency (IC50=27, 40, 13 μM) was shown in the time course suppression of pain, fever, and PGE2 by naproxen [3].

Absorption, Distribution and Excretion
Naproxen is available as a free acid and sodium salt. At comparable doses, (naproxen 500 mg = naproxen sodium 550 mg) they differ slightly in their rates of absorption, but otherwise they are therapeutically and pharmacologically equivalent. Naproxen sodium achieves a peak plasma concentration after 1 hour, while peak plasma concentration is observed after 2 hours with naproxen (free acid). There are no differences between the 2 forms in the post-absorption phase pharmacokinetics. The difference in initial absorption should be considered when treating acute pain, since naproxen sodium may offer a quicker onset of action. The mean Cmax for the various formulations (immediate release, enteric coated, controlled release etc.) of naproxen are comparable and range from 94 mcg/mL to 97.4 mcg/mL. In one pharmacokinetic study, the mean Tmax of naproxen 500 mg (immediate release) given every 12 hours over 5 days was 3 hours, compared to a mean Tmax of 5 hours for Naprelan 1000 mg (controlled release) given every 24 hours over 5 days. In this same study, the AUC0-24hr was 1446mcgxhr/mL for naproxen immediate release and 1448 mcgxhr/mL for the controlled release formulation. A separate study comparing the pharmacokinetics of Naprosyn tablets and EC-Naprosyn observed the following values: Tmax and AUC0-12hrs of EC-Naprosyn were 4 hours and 845 mcgxhr/mL respectively, and Tmax and AUC0-12hrs values of Naprosyn were 1.9 hours and 767 mcgxhr/mL respectively. When given in combination with sumatriptan the Cmax of naproxen is roughly 36% lower compared to naproxen sodium 550 mg tablets, and the median Tmax is 5 hours. Based on the AUC and Cmax of naproxen, Vimovo (naproxen/esomeprazole combination product) and enteric-coated naproxen may be considered bioequivalent. Overall, naproxen is rapidly and completely absorbed when administered orally and rectally. Food may contribute to a delay in the absorption of orally administered naproxen, but will not affect the extent of absorption.
After oral administration, about 95% of naproxen and it's metabolites can be recovered in the urine with 66-92% recovered as conjugated metabolite and less than 1% recovered as naproxen or desmethylnaproxen. Less than 5% of naproxen is excreted in the feces.
Naproxen has a volume of distribution of 0.16 L/kg.
Naproxen is cleared at a rate of 0.13 mL/min/kg.
Oral absorption of naproxen in dogs is rapid, with peak plasma concentration reached in 0.5-3 hr. The reported elimination half-life in dogs is 34-72 hr. Naproxen is highly protein bound (>99.0%). In dogs, naproxen is primarily eliminated through the bile, whereas in other species, the primary route of elimination is through the kidneys. The long half-life of naproxen in dogs appears to be due to its extensive enterohepatic recirculation.
After therapeutic doses, naproxen is more than 99% bound to plasma proteins. When naproxen binding sites become saturated (at twice daily doses of 500 mg or more), plasma free drug concentrations increase and may result in increased urinary clearance rates. Therefore, plasma naproxen concentrations tend to plateau when dosage exceeds 500 mg twice daily. In a study in patients with severe renal failure, binding of naproxen to serum proteins was decreased compared to healthy adults; the decreased binding may have accounted for an increase in metabolism and apparent volume of distribution of the drug observed in these patients. In patients with chronic alcoholic liver disease, total plasma concentrations of naproxen are decreased while concentrations of the unbound drug are increased.
The pharmacokinetics of naproxen, its metabolite 6-hydroxy-alpha-methyl-2-naphthaleneacetic acid (O-desmethylnaproxen), and their acyl glucuronides were studied in 10 subjects (ages 20-50 yr) who received an oral dose of 500 mg naproxen. Mean half-life of naproxen in 9 subjects was 24.7 hr. A half-life of 7.4 hr in the 10th subject was considered an extraordinary case. Naproxen acyl glucuronide accounted for 50.8% of the dose, its isomerized conjugate isoglucuronide for 6.5%, O-desmethylnaproxen acyl glucuronide for 14.3%, and its isoglucuronide for 5.5%. Excretion of naproxen and O-desmethylnaproxen was negligible. Plasma protein binding was 98% for naproxen, 100% for O-desmethylnaproxen, 92% for naproxen acyl glucuronide, 66% for naproxen isoglucuronide, 72% for O-desmethylnaproxen acyl glucuronide, and 42% for O-desmethylnaproxen isoglucuronide. It was concluded that naproxen is O-desmethylated and parent drug and metabolite are conjugated into acyl glucuronides.
The effects of rheumatoid arthritis disease activity on the pharmacokinetics of the highly albumin-bound nonsteroidal anti-inflammatory drug naproxen were studied in six patients during chronic therapy. In the same patients, kinetics during active disease were compared with those in improvement. Active disease is commonly associated with hypoalbuminemia: 30 +/- 4 gm/L vs. 41 +/- 2 gm/L (mean +/- SD) at the time of improvement. Total naproxen concentrations were significantly lower in active disease, together with a larger apparent volume of distribution (10.6 +/- 1.8 L vs. 8.4 +/- 1.3 L; P less than 0.05) and total body clearance (0.79 +/- 1.8 L/hr vs. 0.59 +/- 0.14 L/hr; P less than 0.001). Peak unbound naproxen concentrations were 29% +/- 19% (P less than 0.05) lower at the time of improvement. The unbound clearance was found diminished during active disease (390 +/- 277 L/hr) in comparison with improvement (488 +/- 343 L/hr; P less than 0.05). Clinical implications of the alterations in naproxen kinetics induced by polyarticular inflammation in patients with rheumatoid arthritis are discussed.
For more Absorption, Distribution and Excretion (Complete) data for NAPROXEN (15 total), please visit the HSDB record page.

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Metabolism / Metabolites
Naproxen is heavily metabolized in the liver and undergoes both Phase I and Phase II metabolism. The first step involves demethylation of naproxen via CYP 1A2, 2C8, and 2C9. Both naproxen and desmethylnaproxen proceed to Phase II metabolism; however, desmethylnaproxen can form both acyl and phenolic glucoronide products, while naproxen only produces the acyl glucuronide. The acyl glucuronidation process involves UGT 1A1, 1A3, 1A6, 1A7, 1A9, 1A10 and 2B7, while phenolic glucuronidation is catalyzed by UGT 1A1, 1A7,1A9, and 1A10. Desmethylnaproxen also undergoes sulphation which is mediated by SULT 1A1, 1B1 and 1E1.
Naproxen is extensively metabolized in the liver to 6-desmethylnaproxen. Approximately 95% of the drug is excreted in urine as unchanged naproxen (less than 1%) and 6-desmethylnaproxen (less than 1%) and their glucuronide or other conjugates (66-92%). Some data suggest that renal excretion of unchanged naproxen may be negligible or absent; previously reported concentrations of unchanged drug may reflect rapid hydrolysis of conjugates during collection, storage, and handling of urine samples. The half-life of naproxen metabolites and conjugates is shorter than 12 hours. Naproxen metabolites may accumulate in patients with renal impairment. Elimination of naproxen is reduced in patients with severe renal impairment. A small amount (less than 5%) of the drug is excreted in feces.
The pharmacokinetics of naproxen, its metabolite 6-hydroxy-alpha-methyl-2-naphthaleneacetic acid (O-desmethylnaproxen), and their acyl glucuronides were studied in 10 subjects (ages 20-50 yr) who received an oral dose of 500 mg naproxen. Mean half-life of naproxen in 9 subjects was 24.7 h. A half-life of 7.4 h in the 10th subject was considered an extraordinary case. Naproxen acyl glucuronide accounted for 50.8% of the dose, its isomerized conjugate isoglucuronide for 6.5%, O-desmethylnaproxen acyl glucuronide for 14.3%, and its isoglucuronide for 5.5%. Excretion of naproxen and O-desmethylnaproxen was negligible. Plasma protein binding was 98% for naproxen, 100% for O-desmethylnaproxen, 92% for naproxen acyl glucuronide, 66% for naproxen isoglucuronide, 72% for O-desmethylnaproxen acyl glucuronide, and 42% for O-desmethylnaproxen isoglucuronide. It was concluded that naproxen is O-desmethylated and parent drug and metabolite are conjugated into acyl glucuronides.
Naproxen has known human metabolites that include (2S,3S,4S,5R)-3,4,5-Trihydroxy-6-[(2S)-2-(6-methoxynaphthalen-2-yl)propanoyl]oxyoxane-2-carboxylic acid and O-Desmethylnaproxen.

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Biological Half-Life
The elimination half-life of naproxen is reported to be 12-17 hours.
The reported elimination half-life in dogs is 34-72 hr.
In healthy adults, the plasma half-life of naproxen reportedly ranges from 10-20 hr. The manufacturer state that the plasma half-life of naproxen is about 13 hr. The plasma half-life and elimination of the drug appear to be similar in children and adults.
The pharmacokinetics of naproxen, its metabolite 6-hydroxy-alpha-methyl-2-naphthaleneacetic acid (O-desmethylnaproxen), and their acyl glucuronides were studied in 10 subjects (ages 20-50 yr) who received an oral dose of 500 mg naproxen. Mean half-life of naproxen in 9 subjects was 24.7 hr. A half-life of 7.4 hr in the 10th subject was considered an extraordinary case. ...

Interactions
Methotrexate is a cornerstone in the treatment of juvenile idiopathic arthritis. Although associated with many mild adverse effects, the short and long-term safety of methotrexate in juvenile idiopathic arthritis has been excellent. While many juvenile idiopathic arthritis children treated with methotrexate develop liver enzyme abnormalities, no cases of irreversible liver damage or of severe non-infectious hepatitis with Reye-like features have been reported in non-systemic juvenile idiopathic arthritis. /The investigators/ report a 2-year-old girl with oligoarthritis whose liver enzyme increased to greater than 45 times the upper limit of normal, and developed hypoglycemia and hyperammonemia after 10 months of methotrexate and naproxen therapy. An infectious and metabolic work-up for other causes was unremarkable. She recovered completely after folinic acid therapy; methotrexate and naproxen was not restarted. While very rare in juvenile idiopathic arthritis, methotrexate in synergism with naproxen can induce severe liver toxicity and it is important to screen children for liver enzyme abnormalities.
Because naproxen is highly protein bound, it theoretically could be displaced from binding sites by, or it could displace from binding sites, other protein-bound drugs such as oral anticoagulants, hydantoins, salicylates, sulfonamides, and sulfonylureas. Although no clinically important drug interactions have been reported, patients receiving naproxen with any of these drugs should be observed for adverse effects.
Administration of naproxen with warfarin results in a slight increase in free warfarin in serum, but does not affect the hypoprothrombinemic effect of warfarin. Because naproxen may cause GI bleeding and may inhibit platelet aggregation, the drug should be used with caution in patients receiving any anticoagulant or thrombolytic agent (eg, streptokinase).
Results of a study in patients with diabetes mellitus showed no interference by naproxen on the effect of tolbutamide on plasma glucose concn.
For more Interactions (Complete) data for NAPROXEN (18 total), please visit the HSDB record page.

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Non-Human Toxicity Values
LD50 Mouse iv 435 mg/kg
LD50 Mouse oral 1234 mg/kg
LD50 Mouse ip 500 mg/kg
LD50 Mouse sc 475 mg/kg
For more Non-Human Toxicity Values (Complete) data for NAPROXEN (9 total), please visit the HSDB record page.

[1]. Selectivity of nonsteroidal antiinflammatory drugs as inhibitors of constitutive and inducible cyclooxygenase. Proc Natl Acad Sci U S A. 1993 Dec 15;90(24):11693-7.

[2]. Prevention of bleomycin-induced lung inflammation and fibrosis in mice by naproxen and JNJ7777120 treatment. J Pharmacol Exp Ther. 2014 Nov;351(2):308-16.

[3]. Pharmacokinetic-pharmacodynamic modeling of the inhibitory effects of naproxen on the time-courses of inflammatory pain, fever, and the ex vivo synthesis of TXB2 and PGE2 in rats.

Therapeutic Uses
Anti-Inflammatory Agents, Non-Steroidal; Cyclooxygenase Inhibitors; Gout Suppressants
Naproxen and its salt are used to relieve postoperative pain (including that associated with dental surgery), postpartum pain, primary dysmenorrhea, pain following insertion of an intrauterine contraceptive device, orthopedic pain, headache (including migraine), and visceral pain associated with cancer. Naproxen sodium also may be used for self-medication to provide temporary relief of minor aches and pains associated with the common cold, headache, toothache, muscular aches, and backache. /Included in US product label/
Naproxen has been used in the symptomatic management of osteitis deformans (Paget's disease of bone) and Bartter's syndrome. /Use is not currently included in the labeling approved by the US FDA/
When used in the treatment of rheumatoid arthritis or juvenile rheumatoid arthritis, naproxen has relieved pain and stiffness, reduced swelling, and improved mobility and grip strength. In the treatment of osteoarthritis, naproxen has relieved pain and stiffness and improved knee joint function. Naproxen appears to be only palliative in these conditions and has not been shown to permanently arrest or reverse the underlying disease process. Naproxen sodium also may be used for self-medication to provide temporary relief of minor aches and pains associated with arthritis. /Included in US product label/
For more Therapeutic Uses (Complete) data for NAPROXEN (9 total), please visit the HSDB record page.

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Drug Warnings
Pseudoporphyria is characterized by skin fragility, blistering and scarring in sun-exposed skin areas without abnormalities in porphyrin metabolism. The phenylpropionic acid derivative group of nonsteroidal anti-inflammatory drugs, especially naproxen, is known to cause pseudoporphyria. Naproxen is currently one of the most prescribed drugs in the therapy of juvenile idiopathic arthritis. The prevalence of pseudoporphyria was determined in a 9-year retrospective study of children with juvenile idiopathic arthritis and associated diseases. In addition, /the investigators/ prospectively studied the incidence of pseudoporphyria in 196 patients (127 girls and 69 boys) with juvenile idiopathic arthritis and associated diseases treated with naproxen from July 2001 to March 2002. ... These data /were compared/ with those from a matched control group with juvenile idiopathic arthritis and associated diseases not treated with naproxen in order to identify risk factors for development of pseudoporphyria. The incidence of pseudoporphyria in the group of children taking naproxen was 11.4%. Pseudoporphyria was particularly frequent in children with the early-onset pauciarticular subtype of juvenile idiopathic arthritis (mean age 4.5 years). Pseudoporphyria was associated with signs of disease activity, such as reduced hemoglobin (<11.75 g/dL), and increased leucocyte counts (>10,400/uL) and erythocyte sedimentation rate (>26 mm/hour). Comedications, especially chloroquine intake, appeared to be additional risk factors. The mean duration of naproxen therapy before the onset of pseudoporphyria was 18.1 months, and most children with pseudoporphyria developed their lesions within the first 2 years of naproxen treatment. Juvenile idiopathic arthritis disease activity seems to be a confounding factor for pseudoporphyria. In particular, patients with early-onset pauciarticular juvenile idiopathic arthritis patients who have significant inflammation appear to be prone to developing pseudoporphyria upon treatment with naproxen.
Short-term use of NSAIAs to relieve acute pain, especially at low dosages, does not appear to be associated with an increased risk of serious cardiovascular events (except immediately following coronary artery bypass graft (CABG) surgery). Therefore, in early 2005, the US Food and Drug Administration (FDA) concluded that preparations of NSAIAs (including naproxen) that currently were available without a prescription had a favorable benefit-to-risk ratio when used according to labeled instructions, and determined that these preparations should remain available without a prescription despite the addition of a boxed warning to the professional labeling of prescription-only preparations of these drugs.
With the exception of precautions related to the sodium content of naproxen sodium, the cautions associated with naproxen sodium use are the same as those for naproxen use. Each 275 or 550 mg naproxen sodium tablet contains about 1 or 2 mEq of sodium, respectively, and each mL of the commercially available naproxen suspension contains about 0.34 mEq of sodium; this should be considered in patients whose sodium intake must be restricted. /Naproxen sodium/
Patients should be advised that naproxen, like other nonsteroidal anti-inflammatory agents, is not free of potential adverse effects, including some that can cause discomfort, and that, rarely, more serious effects (e.g., GI bleeding), which may require hospitalization and may even be fatal, can occur. Patients also should be informed that, while nonsteroidal anti-inflammatory agents may be commonly employed for conditions that are less serious, nonsteroidal anti-inflammatory agent therapy often is considered essential for the management of some diseases (eg, rheumatoid arthritis), and the drugs have a major role in the management of pain. Clinicians may wish to discuss with their patients the potential risks and likely benefits of nonsteroidal anti-inflammatory agent therapy, particularly when consideration is being given to use of these drugs in less serious conditions for which therapy without a nonsteroidal anti-inflammatory agent may represent an acceptable alternative to both the patient and clinician.
For more Drug Warnings (Complete) data for NAPROXEN (40 total), please visit the HSDB record page.

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Pharmacodynamics
Naproxen is an established non-selective NSAID and is useful as an analgesic, anti-inflammatory and antipyretic. Similar to other NSAIDs, the pharmacological activity of naproxen can be attributed to the inhibition of cyclo-oxygenase, which in turn reduces prostaglandin synthesis in various tissues and fluids including the synovial fluid, gastric mucosa, and the blood. Although naproxen is an effective analgesic, it can have unintended deleterious effects in the patient. For instance, naproxen can adversely affect blood pressure control. A study found that use of naproxen induced an increase in blood pressure, although the increase was not as significant as that found with ibuprofen use. Further, studies have found that the risk of upper gastrointestinal bleeding is on average four-fold higher for individuals taking NSAIDs. Other factors that increase the risk of upper gastrointestinal bleeding include concurrent use of corticosteroids or anticoagulants, and a history of gastrointestinal ulcers.

C14H14O3

230.2592

230.094

C, 73.03; H, 6.13; O, 20.85

22204-53-1

(±)-Naproxen;23981-80-8;Naproxen sodium;26159-34-2

156391

White to off-white solid powder

1.2±0.1 g/cm3

403.9±20.0 °C at 760 mmHg

152-154 °C(lit.)

154.5±15.3 °C

0.0±1.0 mmHg at 25°C

1.609

3

1

3

3

17

277

1

O(C([H])([H])[H])C1C([H])=C([H])C2C([H])=C(C([H])=C([H])C=2C=1[H])[C@@]([H])(C(=O)O[H])C([H])([H])[H]

CMWTZPSULFXXJA-VIFPVBQESA-N

InChI=1S/C14H14O3/c1-9(14(15)16)10-3-4-12-8-13(17-2)6-5-11(12)7-10/h3-9H,1-2H3,(H,15,16)/t9-/m0/s1

(S)-2-(6-methoxynaphthalen-2-yl)propanoic acid

CG 3117 CG3117 CG-3117 Naproxen Naposin Napratec

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 (~434.29 mM)
H2O : ~75 mg/mL (~325.72 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (10.86 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 (10.86 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 (10.86 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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Solubility in Formulation 4: 2 mg/mL (8.69 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

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