셀레콕시브

Pharmaceuticals -> Listed in ZINC15

Pharmaceuticals -> Used in Switzerland

Pharmaceuticals -> Musculo-skeletal system -> Anti-inflammatory and antirheumatic products

Pharmaceuticals

Breast Feeding; Lactation; Milk, Human; Analgesic Agents; Anti-inflammatory Agents, Nonsteroidal

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

Pharmaceuticals

157-159

157-159 °C

101.7 - 103.9 °C

11.1

pKa = 11.1 (sulfonamide moiety)

187.3 Ų [M+H]+ [CCS Type: DT; Buffer gas: N2; Ionization: ESI+; Dataset: TOXCAST; Source Identifier: DTXSID0022777]

186.4 Ų [M+H]+ [CCS Type: TW; Method: Major Mix IMS/Tof Calibration Kit (Waters)]

206.69 Ų [M+Na]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

186.1 Ų [M+H]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

Danger

H317 (11.9%): May cause an allergic skin reaction [Warning Sensitization, Skin]

P203, P261, P264+P265, P272, P280, P302+P352, P305+P351+P338, P318, P321, P333+P317, P337+P317, P362+P364, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 159 reports by companies from 21 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Danger

H360: May damage fertility or the unborn child [Danger Reproductive toxicity]

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including celecoxib, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide.

Advice for firefighters: Wear self contained breathing apparatus for fire fighting if necessary.

Keep container tightly closed in a dry and well-ventilated place.

Store at room temperature 20 °C to 25 °C (68 °F to 77 °F); excursions permitted between 15 °C to 30 °C (59 °F to 86 °F).

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Use personal protective equipment. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Evacuate personnel to safe areas. Avoid breathing dust. Environmental precautions: Prevent further leakage or spillage if safe to do so. Do not let product enter drains. Discharge into the environment must be avoided. Methods and materials for containment and cleaning up: Pick up and arrange disposal without creating dust. Sweep up and shovel. Keep in suitable, closed containers for disposal.

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

Product: Offer surplus and non-recyclable solutions to a licensed disposal company. Contact a licensed professional waste disposal service to dispose of this material. Dissolve or mix the material with a combustible solvent and burn in a chemical incinerator equipped with an afterburner and scrubber. Contaminated packaging: Dispose of as unused product.

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Use personal protective equipment. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Evacuate personnel to safe areas. Avoid breathing dust. Environmental precautions: Prevent further leakage or spillage if safe to do so. Do not let product enter drains. Discharge into the environment must be avoided.

Precautions for safe handling: Avoid formation of dust and aerosols. Provide appropriate exhaust ventilation at places where dust is formed.

Appropriate engineering controls: Handle in accordance with good industrial hygiene and safety practice. Wash hands before breaks and at the end of workday.

Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands.

SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker.

Eye/face protection: Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU).

Skin protection: Handle with gloves.

Body Protection: Impervious clothing. The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace.

Respiratory protection: Where risk assessment shows air-purifying respirators are appropriate use a full-face particle respirator type N100 (US) or type P3 (EN 143) respirator cartridges as a backup to engineering controls. If the respirator is the sole means of protection, use a full-face supplied air respirator. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU).

Table: Clinically Significant Drug Interactions with Celecoxib [Table#6655]

Metabolism of celecoxib is mediated by the cytochrome P-450 (CYP) isoenzyme 2C9, and the possibility exists that drugs that inhibit this enzyme (e.g., fluconazole, fluvastatin, zafirlukast) may affect the pharmacokinetics of celecoxib. Therefore, celecoxib and drugs that inhibit the CYP2C9 isoenzyme should be administered concomitantly with caution. In addition, celecoxib inhibits CYP2D6, and the possibility exists that celecoxib may alter the pharmacokinetics of drugs metabolized by this isoenzyme, including various beta-adrenergic blocking agents, many tricyclic and other antidepressants, various antipsychotic agents, and some antiarrhythmics (e.g., encainide, flecainide). Results of in vitro studies indicate that celecoxib is not a substrate for CYP2D6, and the drug does not inhibit the CYP2C9, CYP2C19, or CYP3A4 isoenzymes.

Administration of an antacid containing magnesium or aluminum with celecoxib decreased peak plasma concentrations of celecoxib by 37% and the area under the plasma concentration-time curve (AUC) by 10% in clinical studies. However, the manufacturer makes no specific recommendation for administration of the drug with regard to antacids because these effects are not considered clinically important.

Results of clinical studies indicate that clinically important drug interactions may occur if celecoxib is administered with fluconazole. Concomitant administration of celecoxib with fluconazole can result in substantially increased plasma concentrations of celecoxib. This pharmacokinetic interaction appears to occur because fluconazole inhibits the CYP2C9 isoenzyme involved in celecoxib metabolism. In one study, concomitant administration of fluconazole (200 mg daily) and celecoxib (a single 200-mg dose) increased plasma concentrations of celecoxib twofold. The manufacturer of celecoxib states that celecoxib therapy should be initiated at the lowest recommended dosage in patients receiving fluconazole concomitantly.

For more Interactions (Complete) data for Celecoxib (12 total), please visit the HSDB record page.

In clinical studies involving several thousand patients treated for at least 3 months, the rate of serum aminotransferase enzyme elevations above three times the upper limit of the normal range was 1.1% in celecoxib treated compared to 0.9% in placebo treated patients. The ALT elevations that occurred during celecoxib therapy were usually transient and benign, resolving even with continuation of the medication. It is unclear whether such elevations are due to the medication since similar rates of abnormalities are identified in patients with arthritis receiving placebo.

EC50; Species: Ceriodaphnia dubia (Water Flea) age <24 hr; Conditions: freshwater, renewal, pH 7.6-8.8, dissolved oxygen 6.8-9.5 mg/L; Concentration: >1600 ug/L for 7 days; Effect: intoxication, immobilization />98% purity/

EC50; Species: Daphnia magna (Water Flea) age <24 hr; Conditions: freshwater, renewal, pH 7.6-8.8, dissolved oxygen 6.8-9.5 mg/L; Concentration: >890 ug/L for 7 days; Effect: intoxication, immobilization />98% purity/

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 9.7X10+4(SRC), determined from a structure estimation method(2), indicates that celecoxib is expected to be immobile in soil(SRC). Volatilization of celecoxib from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 7.8X10-13 atm-cu m/mole(SRC), estimated using a fragment constant estimation method(3). Celecoxib is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.2X10-9 mm Hg(SRC), determined from a fragment constant method(2). Biodegradation data in soil were not available(SRC, 2005).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 9.7X10+4(SRC), determined from a structure estimation method(2), indicates that celecoxib is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 7.8X10-13 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 90(SRC), from an estimated log Kow of 3.47(2) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is moderate(SRC). Biodegradation data in water were not available(SRC, 2018).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), celecoxib, which has an estimated vapor pressure of 1.2X10-9 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase celecoxib may be removed from the air by wet and dry deposition(SRC). Celecoxib contains chromophores that absorb at wavelengths >290 nm(3) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

Well absorbed in the gastrointestinal tract. When a single dose of 200 mg is given to healthy subjects, peak plasma levels occur 3 hours after an oral dose. The peak plasma level is 705 ng/mL. Absolute bioavailability studies have not been conducted. When multiple doses are given, steady-state is reached on or before Day 5. When taken with a high fat meal, peak plasma levels are delayed for about 1 to 2 hours with an increase in total absorption (AUC) of 10% to 20%.

IDENTIFICATION AND USE: Celecoxib is a pale yellow solid. It is a cyclooxygenase-2 (COX-2) inhibitor used in the management of osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, pain, ankylosing spondylitis, and dysmenorrhea. HUMAN STUDIES: Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events. Allergic reactions, aggravated allergy, bronchospasm, or generalized or facial edema has been reported in 0.1-1.9% of patients receiving celecoxib. Anaphylactoid reactions and angioedema have occurred in patients receiving celecoxib. As with other NSAIDs, anaphylactic reactions have been reported rarely in patients with no previous exposure to the drug. Erythema multiforme, exfoliative dermatitis, Sweet's syndrome, Stevens-Johnson syndrome, and toxic epidermal necrolysis have been reported rarely in patients receiving celecoxib. Hepatitis, jaundice, or liver failure has been reported in patients receiving celecoxib during postmarketing surveillance. Celecoxib may cause premature closure of the ductus arteriosus. ANIMAL STUDIES: Celecoxib was not carcinogenic in rats given oral doses up to 200 mg/kg for males and 10 mg/kg for females, or in mice given oral doses up to 25 mg/kg for males and 50 mg/kg for females for two years. An increased incidence of fetuses with ventricular septal defects, sternebral fusion, rib fusion, and sternebrae abnormality was observed in reproduction studies in rabbits receiving oral celecoxib dosages of 150 mg/kg daily or more throughout organogenesis. A dose-dependent increase in diaphragmatic hernias was observed in rats receiving oral celecoxib dosages of 30 mg/kg or more daily throughout organogenesis. Celecoxib had no effect on male or female fertility or male reproductive function in rats at oral doses up to 600 mg/kg/day. Celecoxib was not mutagenic in an Ames test and a mutation assay in Chinese hamster ovary (CHO) cells, nor clastogenic in a chromosome aberration assay in CHO cells and an in vivo micronucleus test in rat bone marrow.

Unfortunately, no antidote is available for celecoxib overdose. However, celecoxib is a relatively safe medication. There were no reported overdoses of celecoxib during FDA trials, and doses up to 2400 mg per day for 10 days did not result in severe toxicity.

The mechanism of action of celecoxib is believed to be due to inhibition of prostaglandin synthesis. Unlike most NSAIDs, which inhibit both types of cyclooxygenases (COX-1 and COX-2), celecoxib is a selective noncompetitive inhibitor of cyclooxygenase-2 (COX-2) enzyme. It binds with its polar sulfonamide side chain to a hydrophilic side pocket region close to the active COX-2 binding site. Both COX-1 and COX-2 catalyze the conversion of arachidonic acid to prostaglandin (PG) H2, the precursor of PGs and thromboxane.

EPA has released the Interactive Chemical Safety for Sustainability (iCSS) Dashboard. The iCSS Dashboard provides an interactive tool to explore rapid, automated (or in vitro high-throughput) chemical screening data generated by the Toxicity Forecaster (ToxCast) project and the federal Toxicity Testing in the 21st century (Tox21) collaboration. /The title compound was tested by ToxCast and/or Tox21 assays/[USEPA; ICSS Dashboard Application; Available from, as of March 27, 2018: http://actor.epa.gov/dashboard/]

Using a structure estimation method based on molecular connectivity indices(1), the Koc for celecoxib can be estimated to be 9.7X10+4(SRC). According to a classification scheme(2), this estimated Koc value suggests that celecoxib is expected to be immobile in soil.

/SIGNS AND SYMPTOMS/ Celecoxib may cause premature closure of the ductus arteriosus. Avoid use of nonsteroidal anti-inflammatory drugs (NSAIDs), including Celebrex, in pregnant women starting at 30 weeks of gestation (third trimester).

/SIGNS AND SYMPTOMS/ A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs). Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, celebrex is contraindicated in patients with this form of aspirin sensitivity. When celebrex is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma.

/SIGNS AND SYMPTOMS/ Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events.

/SIGNS AND SYMPTOMS/ Allergic reactions, aggravated allergy, bronchospasm, or generalized or facial edema has been reported in 0.1-1.9% of patients receiving celecoxib. Anaphylactoid reactions and angioedema have occurred in patients receiving celecoxib. As with other nonsteroidal anti-inflammatory drugs (NSAIDs), anaphylactic reactions have been reported rarely in patients with no previous exposure to the drug. Erythema multiforme, exfoliative dermatitis, Sweet's syndrome, Stevens-Johnson syndrome, and toxic epidermal necrolysis have been reported rarely in patients receiving celecoxib.

For more Human Toxicity Excerpts (Complete) data for Celecoxib (36 total), please visit the HSDB record page.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including celecoxib, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

M01AH01

M - Musculo-skeletal system

L - Antineoplastic and immunomodulating agents

QL - Antineoplastic and immunomodulating agents

QM - Musculo-skeletal system

Celecoxib inhibits cyclooxygenase 2 (COX-2) enzyme, reducing pain and inflammation. It is important to note that though the risk of bleeding with celecoxib is lower than with certain other NSAIDS, it exists nonetheless and caution must be observed when it is administered to those with a high risk of gastrointestinal bleeding. **A note on the risk of cardiovascular events** Significant concerns regarding the safety of COX-2 selective NSAIDs emerged in the early 2000s. [Rofecoxib], another member of the COX-2 inhibitor drug class, also known as Vioxx, was withdrawn from the market due to prothrombotic cardiovascular risks. Following an FDA Advisory Committee meeting in 2005, in which data from large clinical outcome trials were evaluated, the FDA concluded that the risk for cardiovascular thrombotic events for both COX-2 selective NSAIDs and nonselective NSAIDs was evident. It was determined that the benefits of celecoxib treatment, however, outweighed the risks. Postmarketing cardiovascular outcomes trial (PRECISION) revealed that the lowest possible dose of celecoxib was similar in cardiovascular safety to moderate strength doses of both naproxen and ibuprofen. Patients who had previous cardiovascular events including acute MI, coronary revascularization, or coronary stent insertion were not evaluated in the trial. It is not advisable to administer NSAIDS to these groups of patients.

Unlike most NSAIDs, which inhibit both types of cyclooxygenases (COX-1 and COX-2), celecoxib is a selective noncompetitive inhibitor of cyclooxygenase-2 (COX-2) enzyme. COX-2 is expressed heavily in inflamed tissues where it is induced by inflammatory mediators. The inhibition of this enzyme reduces the synthesis of metabolites that include prostaglandin E2 (PGE2), prostacyclin (PGI2), thromboxane (TXA2), prostaglandin D2 (PGD2), and prostaglandin F2 (PGF2). Resultant inhibition of these mediators leads to the alleviation of pain and inflammation. By inhibiting prostaglandin synthesis, non-steroidal anti-inflammatory drugs (NSAIDs) cause mucosal damage, ulceration and ulcer complication throughout the gastrointestinal tract. Celecoxib poses less of an ulceration risk than other NSAIDS, owing to its decreased effect on gastric mucosal prostaglandin synthesis when compared to placebo. Celecoxib exerts anticancer effects by binding to the cadherin-11 (CDH11)protein, which is thought to be involved in the progression of tumors, and inhibiting the 3-phosphoinositide-dependent kinase-1 (PDK-1) signaling mechanism. In addition, celecoxib has been found to inhibit carbonic anhydrase enzymes 2 and 3, further enhancing its anticancer effects. As mentioned in the pharmacodynamics section of this drug entry, celecoxib may cause an increased risk of thrombotic events. The risk of thrombosis resulting from COX-2 inhibition is caused by the vasoconstricting actions of thromboxane A2, leading to enhanced platelet aggregation, which is uncontrolled when the actions of prostacyclin, a platelet aggregation inhibitor, are suppressed through the inhibition of COX-2.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are well-known causes of acute renal insufficiency and gastropathy in patients with chronic inflammatory diseases. This action is presumed to result from nonselective inhibition of both constitutive and inducible forms of prostaglandin H synthases, also known as the cyclooxygenase enzymes (i.e., COX-1 amd COX-2). Celecoxib (Celebrex) is a COX-2 enzyme inhibitor and has emerged as a preferred therapeutic agent for the treatment of rheumatoid arthritis as compared to other NSAIDs. Celecoxib has recently been the subject of criticism for its side effects, mainly arterial thrombosis and renal hemorrhage, although it is considered a superior drug in protecting the gastrointestinal tract. In the present study, we report that celecoxib not only inhibited COX-2, but also exhibited the property of inhibiting adenylyl cyclase, an important enzyme forming the intracellular second messenger 3',5'-adenosine monophosphate (cAMP) from adenosine triphosphate (ATP). Celecoxib also inhibited cholera toxin-stimulated cAMP formation, which indicated its ability to permeate cell membranes in order to reach intracellular adenylyl cyclase. It inhibited in vitro adenylyl cyclase activity in both human colonic epithelial cells and purified adenylyl cyclase from Bordetella pertussis. The IC50 of celecoxib for B. pertussis adenylyl cyclase was calculated to be 0.375 mM. Lineweaver-Burk analysis showed that the type of enzyme inhibition was competitive. The apparent Km and Vm of adenylyl cyclase was calculated as 25.0 nM and 7.14 nmol/min/mg, respectively. Celecoxib changed the Km value to 66.6 nM without affecting the Vmax. The current study suggests that apart from inflammation, celecoxib therapy could be further extended to diseases involving cAMP upregulation either by endogenous reactions or exogenous agents. These new data showing inhibition of adenylyl cyclase should be considered in light of the drug's pathological effects or in patients specifically excluded from treatment (e.g., asthmatics).

Cardiovascular disease is one of the leading causes of death worldwide, and evidence indicates a correlation between the inflammatory process and cardiac dysfunction. Selective inhibitors of cyclooxygenase-2 (COX-2) enzyme are not recommended for long-term use because of potentially severe side effects to the heart. Considering this and the frequent prescribing of commercial celecoxib, the present study analyzed cellular and molecular effects of 1 and 10 uM celecoxib in a cell culture model. After a 24-hr incubation, celecoxib reduced cell viability in a dose-dependent manner as also demonstrated in MTT assays. Furthermore, reverse transcription-polymerase chain reaction analysis showed that the drug modulated the expression level of genes related to death pathways, and Western blot analyses demonstrated a modulatory effect of the drug on COX-2 protein levels in cardiac cells. In addition, the results demonstrated a downregulation of prostaglandin E2 production by the cardiac cells incubated with celecoxib, in a dose-specific manner. These results are consistent with the decrease in cell viability and the presence of necrotic processes shown by Fourier transform infrared analysis, suggesting a direct correlation of prostanoids in cellular homeostasis and survival.

Celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, has recently been shown to affect the development of different types of cancer. The present study utilized a murine H22 hepatocarcinoma model to investigate the molecular mechanisms involved in celecoxib-induced inhibition of tumor angiogenesis. Tumor-bearing mice were randomly divided into five groups: i) control; ii) low-dose celecoxib (50 mg/kg); iii) high-dose celecoxib (200 mg/kg); iv) 5-fluorouracil (5-FU), (20 mg/kg) and v) combination of 5-FU and celecoxib (50 mg/kg). The antitumor effect of celecoxib was determined by measuring tumor volume. Tumor angiogenesis was evaluated by microvessel density (MVD). Tumor histology and immunostaining for CD34 in endothelial cells were performed to detect MVD. The expression levels of phosphatase and tensin homologue deleted from chromosome 10 (PTEN), phosphatidylinositol 3-kinase (PI3K), phospho-Akt (P-Akt), COX-2, hypoxia-inducible factor-1a (HIF-1a) and vascular endothelial growth factor-A (VEGF-A) were detected by ELISA, immunohistochemistry and western blotting, respectively. We discovered substantial growth delay in murine H22 hepatoma as a result of celecoxib treatment. The inhibition rate of tumor growth induced by high-dose and low-dose celecoxib was 49.3 and 37.0%, respectively (P<0.05). The expression of PI3K, P-Akt, COX-2, HIF-1a, VEGF-A and PTEN in tumor tissues treated with celecoxib was demonstrated by immunohistochemistry, and the MVD was decreased in a dose-dependent manner (P<0.05). Reduced PI3K and P-Akt was particularly apparent in the high-dose celecoxib group (P<0.05). ELISA and western blotting data showed that the expression of PI3K, P-Akt, COX-2, HIF-1a and VEGF-A were reduced and PTEN was increased after treatment with celecoxib. In conclusion, the impact of celecoxib-induced tumor growth delay of murine H22 hepatocarcinoma may correlate with the inhibition of angiogenesis by reducing PI3K, P-Akt, COX-2, HIF-1a and VEGF-A expression and increasing PTEN expression in tumor tissue.

The mechanism of action of Celebrex is believed to be due to inhibition of prostaglandin synthesis, primarily via inhibition of cyclooxygenase-2 (COX-2).

The effective half-life of celecoxib is approximately 11 hours when a single 200 mg dose is given to healthy subjects. The terminal half-life of celecoxib varies because of its low solubility, which prolongs absorption.

A 40 year old woman who was breastfeeding her 5 month old daughter was admitted to the hospital for surgery. In the postoperative period, she received four doses of celecoxib (100 mg twice/day) in addition to other medications. Starting about 5 hours after her last dose, four milk samples were obtained by hand expression over a 24 hour interval. The elimination half life range was 4.0-6.5 hours. ...

The plasma elimination half-life of celecoxib following oral administration of a single 200-mg dose under fasting conditions is about 11 hours, and the apparent plasma clearance of the drug is about 500 mL/minute; these parameters exhibit wide intraindividual variability, presumably because the low aqueous solubility of celecoxib prolongs absorption. The half-life of celecoxib is prolonged in patients with renal or hepatic impairment and has been reported to be 13.1 hours in patients with chronic renal insufficiency and 11 or 13.1 hours in patients with mild or moderate hepatic impairment, respectively.

A large part of celecoxib metabolism is mediated by cytochrome P450 2C9 in the liver with some contribution from CYP3A4 and CYP2C8 and possible contributions from CYP2D6. It is metabolized by biotransformation to carboxylic acid and glucuronide metabolites. Three metabolites, a primary alcohol, a carboxylic acid, and a glucuronide conjugate, have been found in human plasma after celecoxib administration. These are considered inactive metabolites in regards to COX enzyme inhibition. Patients who are known or suspected to have decreased cytochrome P450 2C9 activity or function, based on their previous history, should be administered celecoxib with caution as they may have abnormally high serum concentrations resulting from decreased metabolism celecoxib.

Celecoxib metabolism is primarily mediated via CYP2C9. Three metabolites, a primary alcohol, the corresponding carboxylic acid and its glucuronide conjugate, have been identified in human plasma. These metabolites are inactive as COX-1 or COX-2 inhibitors.

Celecoxib has known human metabolites that include Hydroxy celecoxib.

Hepatic. Celecoxib metabolism is primarily mediated via cytochrome P450 2C9. Three metabolites, a primary alcohol, the corresponding carboxylic acid and its glucuronide conjugate, have been identified in human plasma. CYP3A4 is also involved in the hydroxylation of celecoxib but to a lesser extent. These metabolites are inactive as COX-1 or COX-2 inhibitors. Route of Elimination: Celecoxib is eliminated predominantly by hepatic metabolism with little (<3%) unchanged drug recovered in the urine and feces. 57% of the oral dose is excreted in the feces and 27% is excreted into the urine. The primary metabolite in urine and feces was the carboxylic acid metabolite (73%). The amount of glucuronide in the urine is low. Half Life: The effective half-life is approximately 11 hours when a single 200 mg dose is given to healthy subjects. Terminal half-life is generally variable because of the low solubility of the drug thus prolonging absorption.

JCX84Q7J1L

CELECOXIB

Mechanisms of Action [MoA] - Cyclooxygenase Inhibitors

Chemical Structure [CS] - Anti-Inflammatory Agents, Non-Steroidal

Established Pharmacologic Class [EPC] - Nonsteroidal Anti-inflammatory Drug

Celecoxib is a Nonsteroidal Anti-inflammatory Drug. The mechanism of action of celecoxib is as a Cyclooxygenase Inhibitor.

Anti-inflammatory agents that are non-steroidal in nature. In addition to anti-inflammatory actions, they have analgesic, antipyretic, and platelet-inhibitory actions. They act by blocking the synthesis of prostaglandins by inhibiting cyclooxygenase, which converts arachidonic acid to cyclic endoperoxides, precursors of prostaglandins. Inhibition of prostaglandin synthesis accounts for their analgesic, antipyretic, and platelet-inhibitory actions; other mechanisms may contribute to their anti-inflammatory effects.

A subclass of cyclooxygenase inhibitors with specificity for CYCLOOXYGENASE-2.

Celecoxib is absorbed rapidly in the gastrointestinal tract. When a single oral dose of 200 mg was given to healthy research subjects, the peak plasma levels of celecoxib occurred within 3 hours. The Cmax is 705 ng/mL. When multiple doses are given, steady-state concentrations are reached on or before day 5. When taken with a high-fat meal, peak plasma levels are delayed for about 1 to 2 hours with an increase in total absorption (AUC) of 10% to 20%. The AUC of celecoxib has been shown to be significantly lower in patients with chronic renal impairment. A meta-analysis of pharmacokinetic studies has suggested an approximately 40% higher AUC (area under the curve) of celecoxib in black patients compared to Caucasians for unknown reasons.

Celecoxib is primarily eliminated by hepatic metabolism with small amounts (<3%) of the unchanged drug found in both the urine and feces. About 57% of an oral dose of celecoxib is excreted in the feces and 27% is found to be excreted into the urine in the form of metabolites. The main metabolite in urine and feces is identified as the carboxylic acid metabolite (73%). The amount of glucuronide in the urine is reported to be low.

The apparent volume of distribution of celecoxib at steady state (Vss/F) is about 429 L, which suggests wide distribution into various tissues. Celecoxib is not preferentially bound to red blood cells. Another resource reports a volume of distribution of 455 ± 166L.

Apparent clearance (CL/F), single oral 200 mg dose, healthy subjects = 27.7 L/hr. Clearance may be decreased by about 47% in patients with chronic renal insufficiency, according to a pharmacokinetic study. Studies have not been performed in patients with severe renal impairment.

/MILK/ Limited data from 3 published reports that included a total of 12 breastfeeding women showed low levels of Celebrex in breast milk. The calculated average daily infant dose was 10-40 ug/kg/day, less than 1% of the weight-based therapeutic dose for a two-year old-child.

/MILK/ The aim of this study was to investigate the transfer of celecoxib into human milk. In one group of 3 breastfeeding patients on celecoxib at steady state, milk levels were determined at set intervals over 24 hours. Plasma levels were determined in 2 of their infants, age 17 and 22 months. In a second group of 2 subjects, intravenous lines were placed and a single 200-mg dose of celecoxib was followed by multiple paired plasma and milk samples over 8 hours. The mean milk-to-plasma ratio for celecoxib was 0.23 (95% confidence interval [CI]: 0.15-0.31). The average concentration of celecoxib in milk during the 8-hour dosing interval was 66 ug/L (95% CI: 41-89). The absolute infant dose averaged 9.8 ug/kg/d (95% CI: 6.2-13.4); the mean relative infant dose was 0.30%. Therefore, the average clinical dose transferred to the infant daily would be approximately 0.3% of the weight-adjusted maternal dose. ...

Cyclooxygenase 2 Inhibitors

MEDICATION

Use (kg; approx.) in Germany (2009): >5000

For relief and management of osteoarthritis (OA), rheumatoid arthritis (RA), juvenile rheumatoid arthritis (JRA), ankylosing spondylitis, acute pain, primary dysmenorrhea and oral adjunct to usual care for patients with familial adenomatous polyposis

Condensation of 4-methylacetophenone with ethyl trifluoroacetate in refluxing methanol using sodium methoxide as catalyst gives 4,4,4-trifluoro-1-(4-methylphenyl)butane1,3-dione, which is cyclized with 4-hydrazinophenylsulfonamide in refluxing ethanol.

Methyl trifluoroacetate and 4-methylbenzophenone are refluxed with sodium methoxide in methanol to yield 1-(p-tolyl)-4,4,4-trifluoro-1,3-butanedione. The latter compound is heated with p-hydrazinobenzenesulfonamide, closing the pyrazole ring forming the product.

Preparation: J. J. Talley et al., World Intellectual Property Organization patent 9515316; eidem, United States of America patent 5466823 (both 1995 to Searle) ... .

Information available in 2005 indicated that Celecoxib was used in the manufacture of pharmaceutical preparations in the following countries: Algeria, Argentina, Australia, Austria, Bahrain, Belgium, Brazil, Canada, Chile, Colombia, Costa Rica, Croatia, Cyprus, Czech Republic, Denmark, Egypt, El Salvador, Finland, France, Germany, Guatemala, Honduras, Hong Kong, Hungary, India, Indonesia, Ireland, Israel, Italy, Jordan, Kuwait, Lebanon, Malaysia, Mexico, Netherlands, New Zealand, Nicaragua, Norway, Oman, Panama, Poland, Portugal, Romania, Russian Federation, Saudi Arabia, Singapore, Slovenia, South Africa, Spain, Sweden, Switzerland, Thailand, Turkey, United Arab Emirates, United Kingdom, United States, Yugoslavia (1,2)