Post-marketing research revealed that etodolac's cyclooxygenase inhibition is somewhat selective against COX-2, like to celecoxib and other "COX-2 inhibitors." In contrast to rofecoxib, both etodolac and celecoxib are classified as having "preferential selectivity" toward COX-2 and can fully inhibit COX-1. In hepatoma cells, the r-enantiomer of etodolac (inactive against COX) suppresses the expression of beta-catenin.

Etodolac attenuates paclitaxel-induced peripheral neuropathy by a COX-independent pathway in a mouse model of mechanical allodynia. Etodolac and other NSAIDs inhibits paw swelling and causes gastric mucosal lesions in adjuvant arthritic rats in a dose-dependent manner. Etodolac shows the highest UD(50) value and safety index among these NSAIDs in arthritic rats. Etodolac also shows the highest UD(50) value and safety index, except when its effects are assessed by acetic acid-induced writhing in normal rats. Etodolac dose-dependently inhibits the development of gastric cancer, and no cancer is detected at a dose of 30 mg/kg/day. Etodolac does not affect the extent of inflammatory cell infiltration or oxidative DNA damage, but it significantly inhibits mucosal cell proliferation and dose-dependently represses the development of intestinal metaplasia in the stomachs of Helicobacter pylori (Hp)-infected Mongolian gerbils (MGs). Etodolac alleviates heat-evoked hyperalgesia in the CCI rats and the increase in number of TRAP-positive multinucleated osteoclasts on the CCI-side is abrogated, however, it does not inhibit the decrease of bone mineral content (BMC) and bone mineral density (BMD) on the CCI-side.

Absorption, Distribution and Excretion
Based on mass balance studies, the systemic bioavailability of etodolac from either the tablet or capsule formulation is at least 80%.
It is not known whether etodolac is excreted in human milk; however, based on its physical-chemical properties, excretion into breast milk is expected. Etodolac is extensively metabolized in the liver. The hydroxylated-etodolac metabolites undergo further glucuronidation followed by renal excretion and partial elimination in the feces (16% of dose). Approximately 1% of a etodolac dose is excreted unchanged in the urine with 72% of the dose excreted into urine as parent drug plus metabolite.
390 mL/kg
Oral cl=49.1 mL/h/kg [Normal healthy adults]
Oral cl=49.4 mL/h/kg [Healthy males (18-65 years)]
Oral cl=35.7 mL/h/kg [Healthy females (27-65 years)]
Oral cl=45.7 mL/h/kg [Eldery (>65 years)]
Oral cl=58.3 mL/h/kg [Renal impairement (46-73 years)]
Oral cl=42.0 mL/h/kg [Hepatic impairement (34-60 years)]

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Metabolism / Metabolites
Etodolac is extensively metabolized in the liver. Renal elimination of etodolac and its metabolites is the primary route of excretion (72%). Metabolites found in urine (with percents of the administered dose) are: unchanged etodolac (1%), etodolac glucuronide (13%), hydroxylated metabolites (6-, 7-, and 8-OH; 5%), hydroxylated metabolite glucuronides (20%), and unidentified metabolites (33%). Fecal excretion accounts for 16% of its elimination.
Etodolac has known human metabolites that include (2S,3S,4S,5R)-6-[2-(1,8-Diethyl-4,9-dihydro-3H-pyrano[3,4-b]indol-1-yl)acetyl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid.

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Biological Half-Life
Terminal t_1/2, 7.3 ± 4.0 hours. Distribution t_1/2, 0.71 ± 0.50 hours

Hepatotoxicity
Prospective studies show that 1% to 2% of patients taking etodolac experience at least transient serum aminotransferase elevations. These may resolve even with drug continuation. Marked aminotransferase elevations (>3 fold elevated) occur in
Likelihood score: C (probable rare cause clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Because no information is available on the use of etodolac during breastfeeding, an alternate drug may be preferred, especially while nursing a newborn or preterm infant.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
> 99% bound, primarily to albumin

[1]. Biochemical and pharmacological profile of a tetrasubstituted furanone as a highly selective COX-2 inhibitor. Br J Pharmacol. 1997 May;121(1):105-17.

[2]. Etodolac, a cyclooxygenase-2 inhibitor, attenuates paclitaxel-induced peripheral neuropathy in a mouse model of mechanical allodynia. J Pharmacol Exp Ther. 2012 Jul;342(1):53-60.

[3]. Preventive effects of etodolac, a selective cyclooxygenase-2 inhibitor, on cancer development in extensive metaplastic gastritis, a Helicobacter pylori-negative precancerous lesion. Int J Cancer. 2010 Mar 15;126(6):146.

[4]. Administration of the selective cyclooxygenase (COX)-2 inhibitor etodolac prolongs cardiac allograft survival in a mouse model. Mol Med Report. 2010 Sep-Oct;3(5):771-4.

Etodolac can cause developmental toxicity and female reproductive toxicity according to state or federal government labeling requirements.
Etodolac is a monocarboxylic acid that is acetic acid in which one of the methyl hydrogens is substituted by a 1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl moiety. A preferential inhibitor of cyclo-oxygenase 2 and non-steroidal anti-inflammatory, it is used for the treatment of rheumatoid arthritis and osteoarthritis, and for the alleviation of postoperative pain. Administered as the racemate, only the (S)-enantiomer is active. It has a role as a non-steroidal anti-inflammatory drug, a cyclooxygenase 2 inhibitor, a non-narcotic analgesic and an antipyretic. It is a monocarboxylic acid and an organic heterotricyclic compound.
Etodolac is a non-steroidal anti-inflammatory drug (NSAID) with anti-inflammatory, analgesic and antipyretic properties. Its therapeutic effects are due to its ability to inhibit prostaglandin synthesis. It is indicated for relief of signs and symptoms of rheumatoid arthritis and osteoarthritis.
Etodolac is a Nonsteroidal Anti-inflammatory Drug. The mechanism of action of etodolac is as a Cyclooxygenase Inhibitor.
Etodolac is a nonsteroidal antiinflammatory drug (NSAID) that is available by prescription only and is used long term for therapy of chronic arthritis and short term for acute pain. Etodolac has been linked to rare instances of clinically apparent drug induced liver disease.
Etodolac is a pyranocarboxylic acid and non-steroidal anti-inflammatory drug (NSAID) with antipyretic and analgesic activities. Etodolac inhibits the activity of cyclooxygenase I and II, thereby preventing the formation of prostaglandin which is involved in the induction of pain, fever, and inflammation. It also inhibits platelet aggregation by blocking platelet cyclooxygenase and the subsequent formation of thromboxane A2.
A non-steroidal anti-inflammatory agent and cyclooxygenase-2 (COX-2) inhibitor with potent analgesic and anti-arthritic properties. It has been shown to be effective in the treatment of OSTEOARTHRITIS; RHEUMATOID ARTHRITIS; ANKYLOSING SPONDYLITIS; and in the alleviation of postoperative pain (PAIN, POSTOPERATIVE).

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Drug Indication
For acute and long-term management of signs and symptoms of osteoarthritis and rheumatoid arthritis, as well as for the management of pain.
FDA Label

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Mechanism of Action
Similar to other NSAIDs, the anti-inflammatory effects of etodolac result from inhibition of the enzyme cycooxygenase (COX). This decreases the synthesis of peripheral prostaglandins involved in mediating inflammation. Etodolac binds to the upper portion of the COX enzyme active site and prevents its substrate, arachidonic acid, from entering the active site. Etodolac was previously thought to be a non-selective COX inhibitor, but it is now known to be 5 – 50 times more selective for COX-2 than COX-1. Antipyresis may occur by central action on the hypothalamus, resulting in peripheral dilation, increased cutaneous blood flow, and subsequent heat loss.

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Pharmacodynamics
Etodolac is an anti-inflammatory agent with analgesic and antipyretic properties. It is used to treat osteoarthritis, rheumatoid arthritis and control acute pain. The therapeutic effects of etodolac are achieved via inhibition of the synthesis of prostaglandins involved in fever, pain, swelling and inflammation. Etodolac is administered as a racemate. As with other NSAIDs, the S-form has been shown to be active while the R-form is inactive. Both enantiomers are stable and there is no evidence of R- to S- conversion _in vivo_.

C17H21NO3

287.35

287.152

41340-25-4

(rac)-Etodolac-d3;1276197-46-6

3308

White to off-white solid powder

1.2±0.1 g/cm3

507.9±45.0 °C at 760 mmHg

145-1480C

261.0±28.7 °C

0.0±1.4 mmHg at 25°C

1.597

3.59

2

3

4

21

400

0

NNYBQONXHNTVIJ-UHFFFAOYSA-N

InChI=1S/C17H21NO3/c1-3-11-6-5-7-12-13-8-9-21-17(4-2,10-14(19)20)16(13)18-15(11)12/h5-7,18H,3-4,8-10H2,1-2H3,(H,19,20)

(RS)-2-(1,8-Diethyl-4,9-dihydro-3H-pyrano[3,4-b]indol-1-yl)acetic 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)

Solubility in Formulation 1: ≥ 2.5 mg/mL (8.70 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 (8.70 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 (8.70 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.)