Oxazepam

2.24

log Kow = 2.24 at pH 7.4

2.8

Crystals from alcohol

CREAMY WHITE TO PALE-YELLOW POWDER

less than 1 mg/mL at 66 °F (NTP, 1992)

Soluble in alcohol, chloroform, dioxane

1 G SOL IN MORE THAN 10,000 ML WATER, 220 ML ALCOHOL, 270 ML CHLOROFORM, 2200 ML ETHER

In water, 0.02 g/L at 22 °C

8.81e-02 g/L

401 to 403 °F (NTP, 1992)

205-206 °C

205-206 °C

205 - 206 °C

Oxazepam appears as odorless creamy-white to pale-yellow powder or white crystalline solid. Bitter taste. pH (2% aqueous suspension) 4.8-7. (NTP, 1992)

Solid

STABLE IN LIGHT

STABLE AS SOLID OR IN NEUTRAL SOLN BUT HYDROLYZED BY ACIDS

Warning

H351 (95.7%): Suspected of causing cancer [Warning Carcinogenicity]

P203, P280, P318, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 46 reports by companies from 8 notifications to the ECHA C&L Inventory.；Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown. For more detailed information, please visit ECHA C&L website.

Hazard Traits - Carcinogenicity; Developmental Toxicity；Authoritative List - IARC Carcinogens - 2B; Prop 65；Report - regardless of intended function of ingredient in the product

DEA schedule IV controlled substance

Oxazepam: Does not have an individual approval but may be used under an appropriate group standard

SYMPTOMS: Symptoms of exposure to this compound include sedation, nausea, drowsiness, ataxia and coma (from large doses). Other symptoms include vomiting, lethargy, hyporeflexia, muscular weakness, dysarthria, nystagmus, hypotension, respiratory failure and death from respiratory or cardiac arrest. Exposure can cause syncope, liver damage, bone marrow damage and sensitivity reactions. It can also cause dryness of the mouth, aggressive behavior, blood dyscrasias and hepatic dysfunction. Sleepiness has been reported. It may cause lightheadedness, respiratory depression, constipation, changes in salivation, blurred vision, diplopia, urinary retention, incontinence, mental depression, tremor, headache, confusion, slurred speech, vertigo, changes in libido, blood disorders, jaundice, central nervous system depression and, sometimes, paradoxical reactions such as dysphoria. It may also cause skin rashes (morbilliform, urticarial and maculopapular), dizziness, stimulation of affect, leukopenia, severe rage reactions (rare), menstrual irregularities, change in EEG pattern, agranulocytosis, stupor, disorientation, fever, euphoria, transient amnesia and memory impairment. Exposure to children has resulted in somnolence, changes in REM sleep and loss of muscle control (ataxia). It has also caused lethargy, paradoxical excitation, depressed reflexes, facial edema, delirium, hallucinations and convulsions.；ACUTE/CHRONIC HAZARDS: When heated to decomposition this compound emits very toxic fumes of nitrogen oxides and hydrogen chloride. (NTP, 1992)

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

Schedule IV shall consist of the drugs and other substances, by whatever official name, common or usual name, chemical name, or brand name designated, listed in this section. ... (c) Depressants. Unless specifically excepted or unless listed in another schedule, any material, compound, mixture, or preparation which contains any quantity of the following substances, including its salts, isomers, and salts of isomers whenever the existence of such salts, isomers, and salts of isomers is possible within the specific chemical designation. Oxazepam is included on this list. DEA Controlled Substances Code Number: 2835.

DHHS/NTP; Toxicology and Carcinogenesis Studies of Oxazepam in Swiss-Webster and B6C3F1 Mice (Feed Studies) (1993) TR Rpt No. 443 NIH Pub No.93-3359

Toxicology & Carcinogenesis Studies of Oxazepam in F344/N Rats (Feed Studies) Technical Report Series No. 468 (1998) NIH Publication No. 99-3958 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709

EYES: First check the victim for contact lenses and remove if present. Flush victim's eyes with water or normal saline solution for 20 to 30 minutes while simultaneously calling a hospital or poison control center. Do not put any ointments, oils, or medication in the victim's eyes without specific instructions from a physician. IMMEDIATELY transport the victim after flushing eyes to a hospital even if no symptoms (such as redness or irritation) develop.；SKIN: IMMEDIATELY flood affected skin with water while removing and isolating all contaminated clothing. Gently wash all affected skin areas thoroughly with soap and water. If symptoms such as redness or irritation develop, IMMEDIATELY call a physician and be prepared to transport the victim to a hospital for treatment.；INHALATION: IMMEDIATELY leave the contaminated area; take deep breaths of fresh air. IMMEDIATELY call a physician and be prepared to transport the victim to a hospital even if no symptoms (such as wheezing, coughing, shortness of breath, or burning in the mouth, throat, or chest) develop. Provide proper respiratory protection to rescuers entering an unknown atmosphere. Whenever possible, Self-Contained Breathing Apparatus (SCBA) should be used; if not available, use a level of protection greater than or equal to that advised under Protective Clothing.；INGESTION: DO NOT INDUCE VOMITING. If the victim is conscious and not convulsing, give 1 or 2 glasses of water to dilute the chemical and IMMEDIATELY call a hospital or poison control center. Be prepared to transport the victim to a hospital if advised by a physician. If the victim is convulsing or unconscious, do not give anything by mouth, ensure that the victim's airway is open and lay the victim on his/her side with the head lower than the body. DO NOT INDUCE VOMITING. IMMEDIATELY transport the victim to a hospital.；OTHER: Since this chemical is a known or suspected carcinogen you should contact a physician for advice regarding the possible long term health effects and potential recommendation for medical monitoring. Recommendations from the physician will depend upon the specific compound, its chemical, physical and toxicity properties, the exposure level, length of exposure, and the route of exposure. (NTP, 1992)

SMALL SPILLS AND LEAKAGE: Should a spill occur while you are handling this chemical, FIRST REMOVE ALL SOURCES OF IGNITION, then you should dampen the solid spill material with 60-70% ethanol and transfer the dampened material to a suitable container. Use absorbent paper dampened with 60-70% ethanol to pick up any remaining material. Seal the absorbent paper, and any of your clothes, which may be contaminated, in a vapor-tight plastic bag for eventual disposal. Solvent wash all contaminated surfaces with 60-70% ethanol followed by washing with a soap and water solution. Do not reenter the contaminated area until the Safety Officer (or other responsible person) has verified that the area has been properly cleaned.；STORAGE PRECAUTIONS: You should store this chemical under ambient temperatures and away from acids. This compound is a Schedule IV DEA Controlled Substance and is to be stored according to State and Federal Regulations. Refer to Code of Federal Regulations Title 21 Part 1300 to End. (NTP, 1992)

SRP: The most favorable course of action is to use an alternative chemical product with less inherent propensity for occupational exposure or environmental contamination. Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in soil or water; effects on animal, aquatic, and plant life; and conformance with environmental and public health regulations.

RECOMMENDED RESPIRATOR: Where the neat test chemical is weighed and diluted, wear a NIOSH-approved half face respirator equipped with a combination filter cartridge, i.e. organic vapor/acid gas/HEPA (specific for organic vapors, HCl, acid gas, SO2 and a high efficiency particulate filter). (NTP, 1992)

Induced vomiting and/or gastric lavage should be undertaken, followed by general supportive care, monitoring of vital signs, and close observation of the patient. Hypotension, though unlikely, usually may be controlled with norepinephrine bitartrate Injection. The value of dialysis has not been adequately determined for oxazepam. The benzodiazepine antagonist flumazenil may be used In hospitalized patients as an adjunct to, not as a substitute for, proper management of benzodiazepine overdose. (L1712)

Concurrent use with benzodiazepines may, in theory, competitively inhibit hepatic glucuronidation and decrease the clearance of zidovudine; the toxicity of zidovudine potentially could be increased. /Benzodiazepines/

Concurrent use /of probenecid/ may impair glucuronide conjugation of lorazepam, oxazepam, or temazepam, resulting in increased effects and possibly excessive sedation.

When a benzodiazepine is used with an opioid analgesic, the dosage of the opioid analgesic should be reduced by at least one third and administered in small increments. /Benzodiazepines/

Concurrent use with benzodiazepines may decrease the therapeutic effects of levodopa. /Benzodiazepines/

For more Interactions (Complete) data for OXAZEPAM (10 total), please visit the HSDB record page.

Oxazepam, like other benzodiazepines, is rarely associated with serum ALT or alkaline phosphatase elevations, and clinically apparent liver injury from oxazepam is extremely rare, if it occurs at all. Despite its availability for more than 50 years, there have been no case reports of symptomatic, acute liver injury from oxazepam. Nevertheless, the possibility of liver dysfunction and jaundice are mentioned in the product label for oxazepam. Isolated single cases of clinically apparent liver injury have been reported with other benzodiazepines including alprazolam, chlordiazepoxide, clonazepam, diazepam, flurazepam, lorazepam, and triazolam. The clinical pattern of acute liver injury from benzodiazepines is typically cholestatic and mild-to-moderate in severity with a latency of 1 to 6 months. Fever and rash are uncommon as is autoantibody formation.；Likelihood score: E (unlikely cause of clinically apparent liver injury).

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 390(SRC), determined from a log Kow of 2.24(2) and a regression-derived equation(3), indicates that oxazepam is expected to have moderate mobility in soil(SRC). Volatilization of oxazepam from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 5.5X10-10 atm-cu m/mole(SRC), determined using a fragment constant estimation method(4). Oxazepam is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 4.2X10-12 mm Hg(SRC), determined from a fragment constant method(5). Estimated pKa values of 1.55 (-C=N-) and 10.9 (-OH)(6) indicate that oxazepam will exist in its neutral form under environmentally relevant pH's (pH 5-9)(SRC).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 390(SRC), determined from a log Kow of 2.24(2) and a regression-derived equation(3), indicates that oxazepam is not 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 5.5X10-10 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). Estimated pKa values of 1.55 (-C=N-) and 10.9 (-OH)(5) indicate that oxazepam will exist in its neutral form under environmentally relevant pH's (pH 5-9)(SRC). According to a classification scheme(6), an estimated BCF of 11(SRC), from its log Kow(2) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Oxazepam is not expected to undergo hydrolysis in the environment due to the lack of hydrolyzable functional groups(8).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), oxazepam, which has an estimated vapor pressure of 4.2X10-12 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 oxazepam may be removed from the air by wet and dry deposition(SRC). Oxazepam does not absorb light with wavelengths >290 nm(3), and is not expected to be susceptible to direct photolysis by sunlight(SRC).

Common adverse effects associated with benzodiazepines such as oxazepam may include sedation, fatigue, depression, confusion, memory impairment, dizziness, ataxia, slurred speech, hyper-excitability, nervousness, and weakness. Less frequently encountered adverse effects may involve hypotension, hallucinations, mania, dry mouth, hypersalivation, edema, leukopenia, decreased libido, incontinence, rash, menstrual irregularities, jaundice, and diplopia. Severe adverse effects of oxazepam include respiratory depression and neonatal abstinence syndrome. Anterograde amnesia also has correlations with benzodiazepine use.；Several cases of fixed drug eruptions, which present clinically as well-demarcated oval macules, have been reported in patients taking oxazepam. In these cases, urticaria and diffuse exanthems were not observed. Infrequent cases of QTc prolongation and torsades de pointes have been reported in a retrospective analysis of the postmarketing study; additional research is required.；Drug-Drug interactions；* Patients taking oxazepam for insomnia should avoid caffeine-containing products as they may decrease the efficacy of the drug. Coadministering oxazepam with other CNS depressants such as diphenhydramine or hydrocodone may result in enhancement of CNS effects (eg, severe sedation and respiratory depression). Oxazepam is also not recommended for patients with sleep apnea.；* Concurrent use of opioid agonists such as methadone, morphine, and naltrexone may result in respiratory depression, severe hypotension, and sedation, which is discussed in the box warnings in the Contraindications section.；* The concomitant administration of temazepam with alcohol or other CNS depressants can lead to significant drowsiness, respiratory depression, unconsciousness, and even fatality. Remaining effects on psychomotor and cognitive abilities may result in impaired driving ability and potentially higher risks of falling and hip fractures. Furthermore, the pharmacological activity of oxapeam can be increased by the concurrent use of barbiturates, antipsychotics, skeletal muscle relaxants, and antihistamines.

Well absorbed from the gastrointestinal tract following oral administration however is absorbed at a slower rate compared to other benzodiazepines like diazepam or flurazepam. Time to peak concentration = 2-4 hours. Onset of action is slow, > 3 hours, following oral administration.

Signs and Symptoms of Overdose；A patient with oxazepam overdose typically presents with normal vital signs and severe CNS depression. Clinical symptoms may include ataxia, slurred speech, confusion, drowsiness, and lethargy. Comatose patients are also commonly seen with severe toxicity. Respiratory compromise most commonly occurs when patients intentionally ingest benzodiazepines with another sedative agent, such as an opioid. Oxazepam is the least sedating drug among all benzodiazepines due to slower absorption.；According to the American Heart Association 2023 guidelines, isolated benzodiazepine poisoning rarely results in life-threatening respiratory depression or hemodynamic instability. Therefore, clinicians should consider the possibility of concomitant opioid, alcohol, or other CNS depressant exposure in such cases of poisoning. Respiratory arrest can occur with rapid intravenous (IV) injection or misuse of benzodiazepines via the IV route, particularly when combined with other CNS depressants such as opioids.；Management of Overdose；If toxicity is suspected, rapid, immediate maintenance of airway, breathing, and circulation must be provided. Intubation may be necessary if there is a severe compromise.；If an isolated oxazepam overdose is suspected in a patient with stable hemodynamics and an otherwise unremarkable physical examination, monitoring of vital signs and clinical observation are generally appropriate.；Patients who exhibit respiratory compromise due to oxazepam toxicity may have also taken another drug, such as an opioid. Therefore, it may be appropriate to administer naloxone. Clinicians may administer flumazenil, a competitive benzodiazepine receptor antagonist, to reverse an overdose. However, the administration may precipitate withdrawal seizures in patients who chronically use benzodiazepines and have developed tolerance.

Similar to other benzodiazepines, oxazepam exerts its anxiolytic effects by potentiating the effect of gamma-aminobutyric acid (GABA) on GABA-A receptors through a cooperative mechanism of action. GABA receptors are ionotropic chloride-linked channel receptors that produce inhibitory postsynaptic potentials. When activated by GABA, the GABA receptor/chloride ionophore complex undergoes a conformational change that allows the passage of chloride ions through the channel. Benzodiazepines are believed to exert their effect by increasing the effect of GABA at its receptor. Benzodiazepine binding increases chloride conductance in the presence of GABA by increasing the frequency at which the channel opens. In contrast, barbiturates increase chloride conductance in the presence of GABA by prolonging the time in which the channel remains open. There are 18 subtypes of the GABA receptor subunits. The α₂ subunit of the α₂β₃γ₂ receptor complex is thought to mediate anxiolytic effects while the α₁ subunit of the α₁β₂γ₂ receptor complex is thought to mediate sedative, anticonvulsant and anterograde amnesia effects.

The following link will take the user to the National Toxicology Program (NTP) Test Agent Search Results page, which tabulates all of the "Standard Toxicology & Carcinogenesis Studies", "Developmental Studies", and "Genetic Toxicity Studies" performed with this chemical. Clicking on the "Testing Status" link will take the user to the status (i.e., in review, in progress, in preparation, on test, completed, etc.) and results of all the studies that the NTP has done on this chemical. [http://ntp-apps.niehs.nih.gov/ntp_tox/index.cfm?fuseaction=ntpsearch.searchresults&searchterm=604-75-1]

The Koc of oxazepam is estimated as 390(SRC), using a log Kow of 2.24(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that oxazepam is expected to have moderate mobility in soil.

/SIGNS AND SYMPTOMS/ Benzodiazepines are sedating drugs, which do not usually cause either profound CNS or respiratory depression or any nonsedative effects. Death may occur before hospital arrival due to sedation (particularly if combined with other CNS depressants), but the course of patients reaching hospital is generally uncomplicated. The clinical effects of benzodiazepine poisoning are due entirely to CNS depression. Severe poisoning may occasionally develop hypothermia, bradycardia, and hypotension. Respiratory and CNS depression may lead to aspiration pneumonia. However, deep coma (GCS less than 8) is unusual. Most patients are stuporous or still responsive to painful stimuli unless they have coingested other sedating drugs. Ataxia and nystagmus are common in nontolerant patients, but if pronounced, the possibility of concomitant drug over dose should be raised (i.e., anticonvulsant). /Benzodiazepines/

/SIGNS AND SYMPTOMS/ Signs and symptoms of overdose include somnolence, confusion, coma, hypoactive reflexes, dyspnea, labored breathing, hypotension, bradycardia, slurred speech, and unsteady gait or impaired coordination.

/SIGNS AND SYMPTOMS/ In addition to effects associated with psychological and physical dependence and withdrawal phenomena, chronic oxazepam administration has been associated in very rare cases with jaundice (both hepatocellular and cholestatic), nausea, skin rashes, lowering of blood pressure and, in isolated cases, with the enhancement of parkinsonism or arthritic symptoms.

/CASE REPORTS/ A 75 year-old comatous patient was admitted after ingestion of 200 mg oxazepam. Skin blisters, attributed to oxazepam toxicity, appeared on the left forearm the following day and regressed spontaneously nine days later.

For more Human Toxicity Excerpts (Complete) data for OXAZEPAM (6 total), please visit the HSDB record page.

Hazard Traits - Carcinogenicity; Developmental Toxicity；Authoritative List - IARC Carcinogens - 2B; Prop 65；Report - regardless of intended function of ingredient in the product

DEA schedule IV controlled substance

Oxazepam: Does not have an individual approval but may be used under an appropriate group standard

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

Schedule IV shall consist of the drugs and other substances, by whatever official name, common or usual name, chemical name, or brand name designated, listed in this section. ... (c) Depressants. Unless specifically excepted or unless listed in another schedule, any material, compound, mixture, or preparation which contains any quantity of the following substances, including its salts, isomers, and salts of isomers whenever the existence of such salts, isomers, and salts of isomers is possible within the specific chemical designation. Oxazepam is included on this list. DEA Controlled Substances Code Number: 2835.

N05BA04

N - Nervous system；N05 - Psycholeptics；N05B - Anxiolytics；N05BA - Benzodiazepine derivatives；N05BA04 - Oxazepam

QN - Nervous system；QN05 - Psycholeptics；QN05B - Anxiolytics；QN05BA - Benzodiazepine derivatives；QN05BA04 - Oxazepam

Benzodiazepines, including oxazepam, exert their sedative and anxiolytic effects by potentiating the effects of endogenous GABA, the primary inhibitory neurotransmitter in the CNS. Compared to other benzodiazepines, it has relatively low potency and a moderate duration of action. Oxazepam should be administered with caution to patients for whom a drop in blood pressure may lead to cardiac complications as, in rare cases, it may cause hypotension.

Like other benzodiazepines, oxazepam exerts its anxiolytic effects by potentiating the effect of gamma-aminobutyric acid (GABA) on GABA(A) receptors, the main inhibitory neurotransmitter receptors in the mammalian brain. GABA(A) receptors are a component of GABA-gated ionotropic chloride channels that produce inhibitory postsynaptic potentials - following activation by GABA, the channel undergoes a conformational change that allows the passage of chloride ions through the channel. The inhibitory potentials produced by GABA neurotransmission play an integral role in the suppression and control of epileptiform nerve firing such as that seen in epilepsy, which makes the GABA system a desirable target in the treatment of epilepsy. Benzodiazepines are positive allosteric modulators of GABA(A) function. They bind to the interface between alpha (α) and gamma (γ) subunits on the receptor, commonly referred to as the benzodiazepine binding site, and modulate the receptor such that its inhibitory response to GABA binding is dramatically increased.

The inhibitory neurotransmitter, gamma-aminobutyric acid (GABA), acts on GABAA receptors to regulate vigilance, anxiety, muscle tension, epileptogenic activity and memory functions. Benzodiazepines modulate GABA-evoked chloride currents through a binding site on the GABAA receptor-operated chloride channel. GABA agonists and benzodiazepine agonists simultaneously enhance the binding of the other to its receptor. Benzodiazepine binding appears to shift the GABA receptor from a low affinity state to a high affinity state and also stabilizes the receptor in a conformation that permits the ion channel to remain open. Similarly, GABA binding also enhances benzodiazepine agonist binding to its receptor via the same mechanism. Thus, GABA receptor agonist and benzodiazepine receptor agonists are positive allosteric effectors for each other.

The exact sites and mode of action of the benzodiazepines are unknown. The drugs appear to act at the limbic, thalamic, and hypothalamic levels of the CNS, producing anxiolytic, sedative, hypnotic, skeletal muscle relaxant, and anticonvulsant effects. The effects of benzodiazepines may be mediated through the inhibitory neurotransmitter gamma-aminobutyric acid. Benzodiazepines are capable of producing all levels of CNS depression from mild sedation to hypnosis to coma. /Benzodiazepines/

Anxiolytic and possibly paradoxical CNS stimulatory effects of benzodiazepines are postulated to result from release of previously suppressed responses (disinhibition). After usual doses of benzodiazepines for several days, the drugs cause a moderate decrease in rapid eye movement sleep. Rapid eye movement rebound does not occur when the drugs are withdrawn. Stage 3 and 4 sleep are markedly reduced by usual doses of the drugs; the clinical importance of these sleep stage alterations has not been established. /Benzodiazepines/

Benzodiazepines appear to produce skeletal muscle relaxation predominantly by inhibiting spinal polysynaptic afferent pathways, but the drugs may also inhibit monosynaptic afferent pathways. The drugs may inhibit monosynaptic and polysynaptic reflexes by acting as inhibitory neuronal transmitters or by blocking exitatory synaptic transmission. The drugs may also directly depress motor nerve and muscle function. /Benzodiazepines/

The mean elimination half-life of oxazepam is 8.2 hours.

Considerable variation in the elimination half life has been reported, with mean values ranging from about 5 to about 15 hr. Values of 6.7 hr (range, 5.5-9.2 hr) and 5.8 hr (range, 5.4- 8.4 hr) /were found/ following intravenous and oral administration, respectively. A sex difference has been reported, with a value of 7.8 +/- 0.4 hr (range, 4.9-10.8 hr) in men and 9.7 +/- 0.8 hr (range, 6.3-19.4 hr) in women.

Elimination half-life of oxazepam is 3-21 hr. /From table/

Oxazepam has a single major inactive metabolite, a glucuronide conjugate. The glucuronidation of the S-isomer is catalyzed by UGT2B15. The glucuronidation of the R-isomer is catalyzed by UGT2B7 and UGT1A9.

The metabolism and the anticonvulsant effect of clorazepate were followed for 2 h after its i.v. administration to mice. The ED50 of the drug was 12 mg/kg at 1 min against pentetrazole-induced convulsions (45 mg/kg i.v.), it reached a minimum at 1 hr (2.0 mg/kg) and rose to 2.7 mg/kg at 2 h. The concentrations of unchanged clorazepate and its metabolites, desmethyldiazepam and oxazepam, were determined in plasma and brain after administration of the respective ED50s. Unchanged clorazepate could be detected in plasma for the first hour but never in brain, so it can be considered as inactive pro-drug. The brain concentrations of desmethyldiazepam and oxazepam after the respective ED50s of clorazepate were considerably higher at 1 and 15 min than after longer time intervals. This may be explained by a time lag needed to reach and bind to the benzodiazepine receptor.

... Oxazepam ... /is/ metabolized by direct conjugation with glucuronic acid.

Oxazepam is a commonly used 1,4-benzodiazepine anxiolytic drug that is polymorphically metabolized in humans. However, the molecular basis for this phenomenon is currently unknown. We have previously shown that S-oxazepam glucuronide, the major oxazepam metabolite, is selectively formed by UDP-glucuronosyltransferase (UGT) 2B15, whereas the minor Roxazepam glucuronide is produced by multiple UGTs other than UGT2B15. Phenotype-genotype studies were conducted using microsomes and DNA prepared from the same set of 54 human livers. Sequencing of the UGT2B15 gene revealed three nonsynonymous polymorphisms, D85Y, T352I, and K523T, with variant allele frequencies of 0.56, 0.02, and 0.40, respectively. D85Y genotype showed a significant effect (p = 0.012) on S-oxazepam glucuronidation with lower median activities in 85Y/Y livers (49 pmol/min/mg protein) compared with 85D/D livers (131 pmol/min/mg), whereas 85D/Y livers were intermediate in activity (65 pmol/min/mg). There was also a significant trend (p = 0.049) for higher S-oxazepam activities in the two 352T/I livers (135 and 210 pmol/min/mg) compared with the remaining 352T/T livers (median, 64 pmol/min/mg). Conversely, K523T genotype had no apparent effect on oxazepam glucuronidation (p > 0.05). Donor gender also significantly influenced S-oxazepam glucuronidation with higher median activities in male (65 pmol/min/mg) compared with female (39 pmol/min/ mg) livers (p = 0.042). R-Oxazepam glucuronidation was not affected by either genotype or gender (p > 0.05). In conclusion, gender and D85Y genotype are identified as major determinants of S-oxazepam glucuronidation by human liver and may explain in part polymorphic oxazepam glucuronidation by human subjects.

There are three major pathways of oxazepam metabolism in mice and rats (as in humans): direct conjugation, phenyl ring oxidation and diazepine ring contraction. In mice, conjugation is mainly with glucuronide, predominantly excreted in the urine; in rats, conjugation is mainly with sulfate, which is almost entirely eliminated in the feces. The sulfate conjugate of oxazepam, which is unstable in acidic media, may be the source of the fecal oxazepam It has not been detected in mice. Studies with recirculating, perfused male Swiss (CD-1) mouse liver preparations showed that oxazepam glucuronides are the dominant liver metabolites in this species. Oxazepam can also be conjugated with glucuronide by the placenta of rabbits, apparently in contrast to the human organ. Phenyl ring oxidation is more important in rats than in mice (or humans) and a dihydrodiol (probably the 3',4'- dihydrodiol, since 2'-hydroxy derivatives are not known) accounts for about 30% of the 72-hr urinary metabolites in Fischer 344 rats. This metabolite, which probably forms via an arene oxide intermediate and has not been found in mice, holds implications for the toxicological properties of oxazepam. In rats, ring contraction to 6-chloro-4-phenyl- 2(1H)-quinazoline carboxylic acid occurs to roughly one half of the extent seen in mice.

A method for the extraction of diazepam and its metabolites (nordiazepam, temazepam, and oxazepam) from equine urine and serum and their quantitation and confirmation by liquid chromatography-tandem mass spectrometry is presented. Valium, a formulation of diazepam, was administered at a dose of 10 mg intramuscularly to four standard-bred mares. Diazepam is extensively metabolized in the horse to nordiazepam, temazepam, and oxazepam. Diazepam urinary concentrations were found to be less than 6 ng/mL. Nordiazepam was found to be mainly in its glucuronide-conjugated form and was measured out to a collection time of 53-55 hr. Oxazepam and temazepam were entirely conjugated, and their urinary concentrations were measured out to collection times of 121 hr and 77-79 hr, respectively. Diazepam and nordiazepam were measured in equine postadministration serum out to collection times of 6 and 54 hr, respectively. Oxazepam and temazepam were not detected in postadministration serum.

6GOW6DWN2A

OXAZEPAM

Established Pharmacologic Class [EPC] - Benzodiazepine

Chemical Structure [CS] - Benzodiazepines

Oxazepam is a Benzodiazepine.

OXAZEPAM

Drugs used to induce drowsiness or sleep or to reduce psychological excitement or anxiety.

Agents that alleviate ANXIETY, tension, and ANXIETY DISORDERS, promote sedation, and have a calming effect without affecting clarity of consciousness or neurologic conditions. ADRENERGIC BETA-ANTAGONISTS are commonly used in the symptomatic treatment of anxiety but are not included here.

Substances that do not act as agonists or antagonists but do affect the GAMMA-AMINOBUTYRIC ACID receptor-ionophore complex. GABA-A receptors (RECEPTORS, GABA-A) appear to have at least three allosteric sites at which modulators act: a site at which BENZODIAZEPINES act by increasing the opening frequency of GAMMA-AMINOBUTYRIC ACID-activated chloride channels; a site at which BARBITURATES act to prolong the duration of channel opening; and a site at which some steroids may act. GENERAL ANESTHETICS probably act at least partly by potentiating GABAergic responses, but they are not included here.

Following oral administration, peak plasma levels (Cmax) averaged 450 mg/mL and occurred approximately 3 hours (Tmax) after dosing.

Oxazepam is primarily eliminated in the urine as its glucuronide metabolite, with the feces containing approximately 21% of the unchanged drug. The majority of an orally ingested dose of oxazepam is excreted within 48 hours.

The miniature swine (like humans) eliminated oxazepam primarily as the glucuronides, while aromatic hydroxylation predominated in the rat. In rats, 70.7 +/- 6.0% of a single oral dose of 20 mg/kg bw was eliminated in feces following biliary secretion, while 18.9 +/- 2.4% of the dose was found in the urine. In CD-1 mice given an oral dose of 22 mg/kg bw oxazepam, 57.8% was recovered from the feces and 27.3% was recovered from urine over five days. ... Treatment with 2500 mg/kg diet (ppm) oxazepam in the diet for 14 days before administration of oxazepam by gastric instillation led to a shift from fecal to urinary excretion in mice, but not rats, so that the urinary excretion almost doubled.

Oxazepam accumulates in adipose tissue. /It was/ found that adipose tissue/blood ratios of the drug in mice given 5 mg/kg bw intravenously varied from 1.7 (at 5 min) to 4.9 (at 30 min). Accumulation also occurred in the brain. Maximal concentrations of oxazepam in the brain were 14.3 +/- 0.17 ug/g in mice, 4.5 +/- 0.03 ug/g in rats and 3.5 +/- 0.47 ug/g in guinea-pigs, all at 5 min. Brain/blood drug level ratios in these species varied from 1.1 (at 1 min) to 11.3 (at 10 hr) in mice, from 1.9 (at 1 min) to 6.2 (at 1 hr) in rats and from 1.9 (at 5 min) to 8.9 (at 5 hr) in guinea-pigs.

/It was/ found that the time of maximum absorption of 30 mg oxazepam was 2.2 hr (range, 0.75-4.25 hr) in 18 men and 3.1 hr (range, 0.5-8.0 hr) in 20 women. The maximal plasma concentrations in this study were 622 +/- 37 ng/mL in men and 837 +/- 51 ng/mL in women.

Oxazepam is absorbed fairly rapidly, reaching peak plasma concentrations within 1-4 hr, with a mean of about 2 hr in most studies.

MEDICATION: anxiolytic

Use (kg) in Switzerland (2009): >250；Use (kg; approx.) in Germany (2009): >1000；Use (kg) in USA (2002): 837；Use (kg) in France (2004): 6195；Consumption (g per capita) in Switzerland (2009): 0.032；Consumption (g per capita; approx.) in Germany (2009): 0.012；Consumption (g per capita) in the USA (2002): 0.003；Consumption (g per capita) in France (2004): 0.1；Excretion rate: 1；Calculated removal (%): 23.6

used extensively since the 1960s for the treatment of anxiety and insomnia and in the control of symptoms of alcohol withdrawal. [Wikipedia]

2-Amino-5-chlorobenzophenone is acylated with chloroacetyl chloride & the product is refluxed with sodium iodide to form the iodoacetamido compound. Reaction of one with hydroxylamine effects dehydration & dehydrohalogenation to form the benzodiazepine derivative. Treatment of two with acetic anhydride causes rearrangement to oxazepam which is simultaneously esterified to acetate. Saponification liberates oxazepam.

Information available in 2004 indicated that Oxazepam was used in the manufacture of pharmaceutical preparations in the following countries: Argentina, Australia, Austria, Belgium, Brazil, Canada, Chile, Colombia, Czech Republic, Denmark, Finland, France, Germany, Greece, Ireland, Israel, Italy, Mexico, New Zealand, Norway, Poland, Romania, Singapore, Spain, Sweden, Switzerland, Thailand, United Kingdom, USA (1,2)