3-Ethyl-3-phenyl-2,6-piperidindion

DEA NFLIS-Drug Category -> Depressants and Tranquilizers

DEA Schedule II Controlled Substance -> Depressants

Pharmaceuticals -> Synthetic Cannabinoids or Psychoactive Compounds

log Kow = 1.90

1.90

1.9

Freely soluble in acetone, ethyl acetate, and chloroform; soluble in ethanol and methanol

Soluble in diethyl ether, ethanol.

Highly sol in oil.

In water, 999 mg/L at 30 °C

3.27e-01 g/L

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

Pharmaceuticals

78-81

85-87 °C

MP: 84 °C ... forms a hydrate and a water soluble hydrochloride.

Crystals; mp: 102.5-103 °C; specific optical rotation: 176 deg at 20 °C/D (methanol) /dextro-glutethimide/

Crystals; mp: 102-103 °C; specific optical rotation: -181 deg at 20 °C/D (methanol) /levo-Glutethimide/

84 °C

9.2

pKa = 9.20

Crystals from ether or from ethyl acetate + petroleum ether; mp: 84 °C; max absorption (methanol): 251, 257, 263 nm; freely sol in ethyl acetate, acetone, ether, chloroform; sol in ethanol, methanol; practically insol in water. /dl-Glutethimide/

Warning

H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]

P264, P270, P301+P317, P330, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 41 reports by companies from 1 notifications to the ECHA C&L Inventory.

DEA schedule II controlled substance

2,6-Piperidinedione, 3-ethyl-3-phenyl-: Does not have an individual approval but may be used under an appropriate group standard

Schedules of controlled substances are established by section 202 of the Controlled Substances Act (21 U.S.C. 812). Schedule II. Unless specifically excepted or unless listed in another schedule, any material, compound, mixture, or preparation which contains any quantity of the following substances having a depressant effect on the central nervous system, 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: Glutethimide; DEA Code Number 2550.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies discontinued drug products. Glutethimide is included on this list.

Glutethimide is subject to control under the Federal Controlled Substances Act of 1970 as a schedule (C-II) drug.

A series of glutethimide congeners produce concentration-dependent inhibition of corticosterone production by a suspension of isolated rat adrenal cells. The dextro-rotatory antipode of aminoglutethimide is more potent than its levo enantiomer in inhibiting corticosterone production in this system. Glutethimide, its metabolite glutaconimide, and congeners including those with anti-convulsant activity, 4-hydroxyglutaconimide and 4-aminoglutethimide, have all demonstrated concentration-dependent inhibition of corticosterone production by isolated rat adrenal cells.

The intensity, uniformity and time course of anticoagulant interference by phenobarbital, secobarbital, glutethimide, chloral hydrate and methaqualone were systematically investigated in 16 patients receiving coumarin therapy. Each subject received an individualized fixed daily dose of warfarin and served as his own pre- and postsedative treatment control. Prothrombin times were measured four times weekly during five long-term experiments. Anticoagulant inhibition was observed during the administration of phenobarbital, secobarbital and glutethimide; there was no significant change in prothrombin test results during the trials of chloral hydrate and methaqualone. Barbiturates and glutethimide should not be administered to patients receiving coumarin drugs. The concurrent use of drugs from these groups is decreasing according to a survey of 200 hospital medical records. Chloral hydrate and methaqualone interact pharmacologically with orally administered anticoagulant agents, but the effect is not clinically significant. It is concluded that chloral hydrate and methaqualone may be administered safely without additional caution in prothrombin test monitoring during oral anticoagulant therapy.

Glutethimide, like barbiturates, may induce hepatic microsomal enzymes resulting in increased metabolism of coumarin anticoagulants and decreased anticoagulant response. If a hypnotic is required in patients receiving oral anticoagulants, it is preferable to use an alternative hypnotic (e.g., a benzodiazepine) which does not alter the anticoagulant response. Patients maintained on both glutethimide and a coumarin anticoagulant have a risk of hemorrhage if glutethimide is discontinued and the dosage of the anticoagulant is not adjusted. Glutethimide therapy should not be initiated or discontinued in patients receiving oral anticoagulants without careful attention to the possible need for adjusting anticoagulant dosage.

Concomitant administration of glutethimide and tricyclic antidepressants such as amitriptyline or imipramine may produce additive anticholinergic effects. Although additive anticholinergic effects are usually minor, the possibility of precipitating adynamic ileus, urinary retention, or acute glaucoma, especially in elderly patients, should be considered.

For more Interactions (Complete) data for GLUTETHIMIDE (7 total), please visit the HSDB record page.

Glutethimide is distributed into breast milk ; use by a breast-feeding woman may cause sedation in the infant.

EXPERIMENTAL: Small amounts of the unchanged drug are excreted in breast milk.

IDENTIFICATION: Glutethimide is used as a hypnotic agent. Glutethimide is colorless or white, odorless crystals or powder. It is practically insoluble in water, soluble in ethanol, chloroform and ether. Freely soluble in acetone and ethyl acetate and soluble in methyl alcohol. Stability: at pH 5 the chemical half life was 28.3 years at 25 °C and 1.02 months at pH 8, the decomposition being due to hydrolysis. Indications: Used as an hypnotic in insomnia but rarely as a sedative, glutethimide was initially believed to be almost free from side effects. However, further experience of its toxicity and because its dependence liability, glutethimide has been banned in many countries and many companies have stopped production. HUMAN EXPOSURE: Main risks and target organs: The main target organ is the central nervous system causing coma with fluctuations in depth, and various degrees of hypotension. Anticholinergic effects often occur. Summary of clinical effects: At lower doses, acute intoxication may cause somnolence, ataxia, tonic muscle spasms and abnormal reflexes. In severe intoxication, hypotension, hypothermia, shock, coma, respiratory depression and acidosis may occur. Effects on other organs are usually secondary to coma and shock. Contraindications: Glutethimide is contraindicated in porphyria. Due to its anti-muscarinic action, it should be given with great care to patients with closed-angle glaucoma, prostatic hypertrophy or urinary tract obstruction, and certain cardiac arrhythmias. Alcohol enhances absorption and the hypnotic effects of glutethimide. Like barbiturates, glutethimide induces microsomal hepatic enzymes and enhances the metabolism of coumarin anticoagulants and other drugs, lowering their plasma concentrations. Chronic administration of glutethimide may also enhance vitamin D metabolism. Absorption by route of exposure: Oral: In six healthy volunteers given a dose of 500 mg, absorption was irregular and peak plasma concentrations occurred over one to six hours. However, in four of the six subjects absorption was biphasic. Erratic absorption may be due to the poor solubility of glutethimide in water. Distribution by route of exposure: Oral: following oral administration of 500 mg of glutethimide to healthy subjects, peak plasma concentrations were achieved within two to six hours. Plasma protein binding of glutethimide was about 50%. Glutethimide concentrations were found in the breast milk of 13 nursing mothers given glutethimide. Glutethimide is highly lipophilic and rapidly concentrates in brain and adipose tissue. Biological half-life by route of exposure: Oral: The elimination half-life is 10 to 12 hours, but may increase in severe poisoning. In six healthy subjects, initial half-lives after ingestion were 2.7 to 4.3 hours and subsequent half-lives ranged from 5.1 to 22 hours. Metabolism: Glutethimide is partially metabolized by hydroxylation into 4-hydroxy-2-ethyl-2-phenylglutarimide. In the mouse, this appears to be twice as potent as the parent compound in mice and is believed to contribute to prolonged coma following overdosage. Hydroxylated metabolites are conjugated and excreted mainly in the urine but also in bile. Elimination by route of exposure: Oral: glutethimide is inactivated by conjugation and the metabolites are excreted in urine, only 2% of the parent substance is excreted in urine, up to 2% of the dose has been reported to be found in the feces. Mode of action: Toxicodynamics Pharmacodynamics: Glutethimide directly blocks electron transfer in cellular respiration. Teratogenicity: There is no evidence of teratogenicity from therapeutic use. Interactions: The effects of glutethimide are additive with those of benzodiazepines, barbiturates, codeine and other CNS depressants. Concomitant administration of antidepressants, antiparkinsonian drugs or other anticholinergic agents may cause additive anticholinergic effects such as urinary retention, exacerbation of glaucoma, or adynamic ileus. Ethanol enhances the effects of glutethimide. Glutethimide induces the hepatic metabolism of some drugs, such as dicoumarol derivatives, the dose of drugs taken concomitantly may require adjustment. Main adverse effects: Common adverse effects are as follows: nausea, headache, hangover, blurred vision, occasional skin rashes, blood disorders (megaloblastic anemia). Osteomalacia peripheral neuropathy and cerebral impairment after prolonged use may also occur. Glutethimide is a drug of abuse and may cause dependence. Acute poisoning: Ingestion: Ingestion is the only route by which acute poisoning may occur. Mild intoxication with small doses results in somnolence, ataxia, tonic muscle spasms, abnormal reflexes. In severe intoxication coma, hypotension, hypothermia, shock, respiratory depression and cerebral edema may occur. Signs from other organs and systems are usually secondary to coma and shock. Chronic poisoning: Ingestion: Ingestion is the only route of glutethimide administration in humans. Prolonged use of the drug may cause peripheral neuropathy, hypocalcemia. Acute abstinence syndrome following glutethimide withdrawal has been described. Chronic ingestion of high doses is associated with impaired memory, inability to concentrate, ataxia, tremors, hyporeflexia, slurring of speech and convulsions. Course, prognosis, cause of death: Any acute poisoning without loss of consciousness may be regarded as mild and the patient is not at risk. The occurrence of coma, hypotension, hypothermia, shock, respiratory depression and complications such as pneumonia mean that glutethimide poisoning is potentially serious. However, death is unusual provided intensive care when needed. Cerebral edema may be fatal. Systematic description of clinical effects Cardiovascular: Hypotension, shock and tachycardia have been observed. Unexplained dysrhythmias may be due to the antimuscarinic effects of the drug or low plasma calcium concentrations. Respiratory: Respiratory depression with intermittent apnea and or arrest may occur in very severe cases. Pneumonia due to aspiration and pulmonary oedema have been reported. Neurological: Central Nervous System (CNS): Various degrees of CNS depression may occur, ranging from lethargy to deep coma. Cerebral edema, intracranial hemorrhage, tonic muscle spasms and hyperreflexia may occur. Truncal ataxia has been reported in acute glutethimide intoxication in children. Peripheral nervous system: Peripheral neuropathy and diplopia has been reported following chronic use. Autonomic nervous system: Glutethimide has antimuscarinic/anticholinergic activity, tachycardia, dryness of mouth, mydriasis, irritability, urinary retention and constipation. Skeletal and smooth muscle: Tonic muscle spasm and paralytic ileus (adynamic ileus) may also be observed. Gastrointestinal: Gastrointestinal atony due to parasympatholytic activity may occur. Urinary: Renal: With the exception of possible pre-renal uremia due to severe hypotension, no other renal effects occur. Other: Urinary retention may occur due to the anticholinergic effect of glutethimide. Dermatological: Bullous changes resembling those seen in barbiturate poisoning and erythematous vesicles have been described. Eye, ear, nose, throat: local effects: Mydriasis and papilloedema have been observed. Hematological: Significant methemoglobinemia has been reported rarely. In a further case, megaloblastic anemia, thrombocytopenia and aplastic anemia occurred. Metabolic: Acid-base disturbances: Acid base disturbances may occur secondary to coma or shock. Fluid and electrolyte disturbances: Hypocalcaemia has been described. Others: Hypothermia has been described. Special risks: Glutethimide readily crosses the placenta and may cause neonatal respiratory depression and neonatal withdrawal symptoms. Eight to 12 hours after a maternal dose of glutethimide. It was found in breast milk. ANIMAL/PLANT STUDIES: Parenteral: following intraperitoneal administration of glutethimide in rats, most of drug was found in the brain and spinal cord and other fat-containing tissues after 20 minutes.

/HUMAN EXPOSURE STUDIES/ Of 22 patients dosed with between 3 and 30 g, 4 patients died (having ingested 10 g, 12 g, 15 g, and 20 g, respectively) with the respective causes of death being irreversible shock, pneumonia, respiratory arrest, and cardiac arrest. A seriously toxic (potentially lethal) serum level of glutethimide is 3 mg/dl or greater, and reported fatal serum levels of glutethimide range between 2 and 88 mg/dL.

/HUMAN EXPOSURE STUDIES/ Potential predictors of outcome following acute glutethimide overdosage were assessed in 63 patients hospitalized with this diagnosis at a large urban medical center between 1962 and 1975. Their mean age was 34 years (range, 15 to 84 years) and 62% were female. Assisted ventilation was required in 59% of cases, and 32% developed hypotension. Six patients died, including all three aged 60 years or older. Multiple regression analysis confirmed that age was the major identifiable determinant of survival, regardless of other factors. Among identifiable determinants of coma grade, glutethimide dose, glutethimide plasma concentration, and coingestion of barbiturates were the most important. An ingested dose of 10 g or more, or a plasma concentration exceeding 30 ug/mL, was almost always associated with deep coma. However, a relatively small ingested dose or a low plasma level by no means ruled out development of serious intoxication, particularly in those patients who also ingested barbiturates. Thus elderly individuals are at high risk for fatal outcome following glutethimide overdosage and should receive priority for intensive care and monitoring. Glutethimide dose, plasma concentration, and history of coingestion of barbiturates are of value in predicting development of deep coma. These items of information should be obtained on admission whenever possible.

/SIGNS AND SYMPTOMS/ Symptoms of chronic toxicity may include toxic psychosis manifested by confusion, delirium and hallucinations, ataxia, tremor, hyporeflexia, slurred speech, memory loss, inability to concentrate, mydriasis, dryness of the mouth, peripheral neuropathy, and osteomalacia. Sudden discontinuation of the drug in physically dependent patients may produce severe withdrawal symptoms including nausea, vomiting, nervousness, tremulousness, tachycardia, abdominal cramps, fever, chills, numbness of extremities, dysphagia, delirium, hallucinations and seizures clinically indistinguishable from generalized tonic-clonic (grand mal) seizures. Neonates born to women dependent on glutethimide may also exhibit withdrawal symptoms.

/SIGNS AND SYMPTOMS/ Glutethimide overdosage produces symptoms similar to those of barbiturate overdosage and may include prolonged coma (which may last several days), hypotension (often more severe than that associated with barbiturate intoxication), respiratory depression (usually less severe than that associated with barbiturate overdosage), shock, and hypothermia which may be followed by fever. The degree of CNS depression often fluctuates, possibly due to irregular absorption of the drug and/or accumulation of an active metabolite. Inadequate ventilation, even without significant respiratory depression, is often a problem and may be accompanied by cyanosis and/or sudden apnea. Dryness of the mouth, widely dilated and fixed pupils, adynamic ileus, and urinary bladder atony may also occur. Other symptoms of glutethimide intoxication include depressed or absent deep tendon and corneal reflexes and diminished or absent pain and pupilary response. Intermittent spasticity of extremities and flaccid paralysis may occur. Various complications including pulmonary edema, cerebral edema, severe infections, pyelonephritis, and acute renal tubular necrosis may occur. Death may result from hypotension, respiratory failure, cerebral edema, or complications of prolonged coma. Ingestion of 5 g of glutethimide usually produces severe intoxication in adults, and the ingestion of 10-20 g of the drug is frequently lethal. Although glutethimide blood concentrations greater than 10 ug/mL are generally associated with intoxication, there is a poor correlation between glutethimide plasma concentration and the clinical course of the patient, possibly because of the formation and accumulation of an active metabolite, 4-hyroxy-2-ethyl-2-phenylglutarimide (4-HG).

For more Human Toxicity Excerpts (Complete) data for GLUTETHIMIDE (16 total), please visit the HSDB record page.

Drug-Induced Liver Injury Severity and Toxicity (DILIst)

glutethimide

DILI Positive

DOI:10.1016/j.drudis.2019.09.022

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ /It was/ reported that a diet containing 0.4% glutethimide fed during pregnancy failed to produce defects in the rat fetus. Double vertebral centra which occurred in 4 of 17 fetuses represent probably only a delay in ossification. /Experiments/ produced resorptions but no congenital defects in the rabbit, mouse and rat.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ ... Pregnant rats /were injected/ (with 200-400 mg/kg /glutethimide/ on days 14 and 15) and ... some behavioral abnormalities /were observed/ in the first progeny of animals under test.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ After administration to rats in a dose of 200-400 mg/kg on days 14 and 15 of the pregnancy the hypnotic drug glutethimide induces in the rat progeny variations in the orienting-motor activity, latent period of runnings and raises the frequency of urinations upon training in a maze. The effect of glutethimide on the orienting-motor behavior was seen only in the first generation of the animals and was absent from the second generation animals.

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ The aromatase inhibitor, aminoglutethimide, causes a blood dyscrasia in about 1% of women taking the drug for the treatment of advanced breast cancer. The parent compound, glutethimide, is known not to possess this toxic action. The effect of both drugs on bone (femur) marrow cells of mice and rats was examined ... For the in vivo study, glutethimide and aminoglutethimide were given orally (50 mg/kg, daily). After 3 wk of this regimen in mice, there was a significant fall (about 50%) in both white blood cell and platelet counts. This is similar to the blood picture changes induced by aminoglutethimide in women. No hematological effects were observed in rats receiving this drug and glutethimide was without effect in either species.

/ALTERNATIVE and IN VITRO TESTS/ The aromatase inhibitor, aminoglutethimide, causes a blood dyscrasia in about 1% of women taking the drug for the treatment of advanced breast cancer. The parent compound, glutethimide, is known not to possess this toxic action. The effect of both drugs on bone (femur) marrow cells of mice and rats was examined by means of standard methods for the colony forming assay for granulocyte-macrophage (GM-CFC) and erythroid cells (CFU-E). There were no significant effects on the cell colonies up to drug concentrations of at least 10 ug/mL. However, above this level concentration-dependent effects were observed. For mouse GM-CFC, 50 and 30% of the cell colonies died when incubated with glutethimide (33 ug/mL) and aminoglutethimide (100 ug/mL), respectively. Similar results for the two drugs were obtained with the mouse CFU-E and with both cell types from the rat. The results indicate that the inhibitory effects were most likely to be non-specific. ... It is proposed that N-hydroxylation of aminoglutethimide, which proceeds in mouse and man but not rat, is an important step in the toxic mechanism.

To enhance elimination- In severe glutethimide overdosage, in addition to supportive measures and symptomatic treatment, hemodialysis or hemoperfusion should be considered in Grade III or Grade IV coma, when renal shutdown or impaired renal function is manifest, and in life-threatening conditions complicated by pulmonary edema, heart failure, circulatory collapse, significant liver disease, major metabolic disturbance, or uremia. Although aqueous hemodialysis is less effective for glutethimide than for readily water-soluble compounds, glutethimide blood concentrations may be decreased more rapidly with hemodialysis and the duration of coma may be shortened; however, the efficacy of this procedure is controversial. Peritoneal dialysis removes some glutethimide; however, it is minimally effective. Charcoal hemoperfusion has been reported to be more effective than hemodialysis. Also, resin hemoperfusion has been reported to be more effective than hemodialysis, especially in patients with life-threatening coma and lethal blood concentrations of intoxicant drugs. Drug extraction techniques should be continued for at least 2 hours after the patient regains consciousness since glutethimide is highly lipid soluble and, therefore, rapidly accumulates in lipoid tissue. As glutethimide is removed from the bloodstream by any technique, it is gradually released from fat storage back into the bloodstream. After substantial amounts of glutethimide have been extracted, this blood-concentration rebound may cause coma to persist or recur.

Specific treatment: If coma is prolonged, appropriate antibiotic therapy is indicated if pulmonary or other infection occurs. Monitoring: Continuous electrocardiogram monitoring should be done to detect arrhythmias. Urinary output should be monitored and maintained, if coma is prolonged. Supportive care: Cardiopulmonary supportive measures should be used and include: maintenance of a patent airway with assisted ventilation, if necessary; monitoring of vital signs and level of consciousness; continuous electrocardiogram to detect arrhythmias; and maintenance of blood pressure with plasma volume expanders and, if necessary, pressor agents. Adequate respiratory gas exchange should be maintained and may require tracheostomy and mechanical assistance. If coma is prolonged, urinary output should be monitored and maintained while preventing overhydration, which might contribute to pulmonary or cerebral edema.

Severe poisoning with coma always needs intensive care. It is essential to maintain a clear airway and provide oxygen. Perform endotracheal intubation and support ventilation. Frequent change of the position of the patient and vigorous physiotherapy are indicated to prevent pneumonia and pulmonary infarctions. Pneumonia must be treated with appropriate antibiotics. Maintain one central or peripheral intravenous route. Administer intravenous fluids in amounts adequate to maintain daily diuresis of two to three liters. Urinary catheterization is necessary in the comatose patient to measure hourly urine output and obtain urine samples. In case of significant hypotension, hypovolemia must be considered as a possible cause and be corrected. If hypotension is severe, infusion of dopamine may be required Monitoring of central venous pressure, and if possible pulmonary artery pressures is indicated. Papilledema or other signs of cerebral edema may indicate the need for mannitol 20%. Correct acidosis.

Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/

For more Antidote and Emergency Treatment (Complete) data for GLUTETHIMIDE (6 total), please visit the HSDB record page.

LD50 Dog oral 500 mg/kg

LD50 Mouse ip 208 mg/kg

LD50 Mouse oral 360 mg/kg

LD50 Rat oral 600 mg/kg

Schedules of controlled substances are established by section 202 of the Controlled Substances Act (21 U.S.C. 812). Schedule II. Unless specifically excepted or unless listed in another schedule, any material, compound, mixture, or preparation which contains any quantity of the following substances having a depressant effect on the central nervous system, 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: Glutethimide; DEA Code Number 2550.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies discontinued drug products. Glutethimide is included on this list.

Glutethimide is subject to control under the Federal Controlled Substances Act of 1970 as a schedule (C-II) drug.

N - Nervous system

QN - Nervous system

Glutethimide seems to be a GABA agonist which helps induce sedation. It also induces CYP 2D6. When taken with codeine, it enables the body to convert higher amounts of codeine (higher than the average 5 - 10%) to morphine. This combination of effects enhances sedation.

Glutethimide has CNS depressant effects similar to those of the barbiturates. The mechanism of action of the drug is not known. In doses used for hypnosis, glutethimide produces cerebral depression and quiet, deep sleep. Like barbiturates, usual hypnotic doses of glutethimide significantly suppress rapid eye movement (REM) or dreaming stage of sleep. Although some tolerance develops to the REM-suppressant effects during intermediate-term chronic administration, REM rebound occurs when the drug is withdrawn, and the patient may experience markedly increased dreaming, nightmares, and/or insomnia.

Glutethimide exhibits anticholinergic activity manifested by mydriasis and inhibition of salivary secretions and intestinal motility. Toxic doses of the drug often produce marked mydriasis, adynamic ileus, and urinary bladder atony. Hypnotic doses of glutethimide do not produce reliable analgesic, antipyretic, anticonvulsant, antiemetic, or antitussive effects. Glutethimide induces liver microsomal enzymes and thus may alter the metabolism of other drugs.

Glutethimide directly blocks electron transfer in cellular respiration.

10-12 hours

Half-life about 10 to 12 hours.

The decline of serum concentrations of glutethimide is biphasic; the half-life for the first phase is about 4 hrs and the half-life for the second phase is 10-12 hours. The apparent serum half-life of the drug in patients severely intoxicated with glutethimide has been reported to be prolonged, but this may have been due to continued absorption of the drug.

In a series of patients with glutethimide overdose, mean serum half-life has been found to be prolonged to around 40.1 hr. The definition of biologic half-life for glutethimide is somewhat difficult because of the rapidly appearing inactive metabolites (glucuronides). The half-life of the inactivated dose (effective biologic half-life) and the time when half of the dose is excreted (maximal biologic half-life) are different; the effective biologic half-life is approximately 10 hr, and the maximal biologic half-life is approximately 16 hr.

The spontaneous decline of glutethimide blood levels follows a biphasic curve, with an initial rapid phase and a later slow phase. During the initial rapid phase, a mean serum half-life of 3.9 hr is obtained... The decline in drug concentration during the second, slower phase gives a mean serum half-life of 11.6 hr, this being brought about by loss of drug from tissue compartments and blood (or central compartment) through metabolism and excretion.

Hepatic. Glutethimide is almost completely metabolized.

Hepatic biotransformation. Glutethimide is almost completely metabolized.

The metabolic fate of glutehimide has not been completely elucidated, particularly following toxic doses of the drug. There is considerable evidence that therapeutic doses of glutethimide are almost completely metabolized in the liver by hydroxylation of the ethyl side chain (levorotatory isomer) and excreted in urine chiefly as glucuronides. About 2% of a dose is metabolized to glutaconimide which has some hypnotic activity. ... 4-Hydroxy-2-ethyl-2 phenylglutarimide is a metabolite which accumulates in the plasma and tissues (including the brain) of patients who have ingested large doses of glutethimide. Several phenolic metabolites and others yet to be identified have been found in urine following acute glutethimide overdosage.

Although glutethimide blood concentrations greater than 10 ug/mL are generally associated with intoxication, there is a poor correlation between glutethimide plasma concentration and the clinical course of the patient, possibly because of the formation and accumulation of an active metabolite, 4-hyroxy-2-ethyl-2-phenylglutarimide.

Glutethimide has an asymmetric carbon atom and gives two optical isomers, both of which are metabolized in a different fashion. The D-isomer is hydrolyzed at the glutarimide ring, loses water, and breaks down into alpha-phenyl-alpha-ethylglutaconimide, which is excreted in the urine as a nonconjugated metabolite in approximately 2% of the administered dose. A major portion of the hydrolyzed D-isomer is combined with glucuronic acid and is excreted in the urine in approximately 45% of the administered dose. The L-isomer is hydrolyzed with release of acetaldehyde from a-phenyl glutarimide. This metabolite is isolated in the urine in approximately 4 percent of the administered dose. The remaining major portion is also combined with glucuronic acid and is excreted in the urine in approximately 45 % of the administered dose. Both glucuronides are water soluble but not fat soluble and no longer possess sedative activity.

For more Metabolism/Metabolites (Complete) data for GLUTETHIMIDE (7 total), please visit the HSDB record page.

Variable

glutethimide is inactivated by conjugation and the metabolites are excreted in urine, only 2% of the parent substance is excreted in urine, up to 2% of the dose has been reported to be found in the faeces.

Glutethimide appears to be irregularly absorbed from the GI tract. Plasma concentrations of the drug required for sedative or hypnotic effects are not known. In limited studies, oral administration of 500 mg and 1 g single doses of glutethimide produced peak plasma concentrations of 2.9-7.1 ug/mL and 6.2-6.8 ug/mL, respectively, within 1-6 hours. The onset of action of glutethimide is rapid; sleep is usually induced within 30 minutes and lasts 4-8 hours following usual hypnotic doses.

Once absorbed, glutethimide quickly becomes concentrated in organs containing fat such as brain and adipose tissues, with a volume of distribution larger than that of whole body water. The drug recirculates from fat stores and is carried to the liver where it undergoes biotransformation, somewhat reminiscent of redistribution of ultra short acting barbiturates like thiopental.

Distribution studies indicate that there is extensive tissue localization of glutethimide, particularly in adipose tissue. In addition, glutethimide (and/or its metabolites) has been detected in liver, kidneys, brain, and bile. Glutethimide crosses the placenta, and small quantities of the drug are distributed into milk. When 1 g doses of glutethimide were administered to pregnant women 2 hours before delivery, maternal and neonatal plasma concentrations of glutethimide were essentially the same immediately after delivery.

In vitro, about 54% of the drug appears to be bound to plasma proteins.

THERAP CAT: Sedative; hypnotic

/Glutethimide/ is effective in inducing sleep that lasts through the night and is also suitable as a daytime sedative. Prolonged administration causes habituation and addiction.

MEDICATION