Extensively metabolized through a complex pathway of biotransformation involving N-dealkylation and reduction. Many of these metabolites are biologically active and may participate in the therapeutic action of diethylpropion.
... Rapidly & extensively metabolized in man, & urinary excretion of unchanged drug & metabolites is practically complete within 30 hr of oral dose. Low recovery & rapid clearance of unchanged drug provide evidence that anorectic activity ... is due mainly to metabolites.
Diethylpropion is aromatic ketone metab by 2 principal routes: n-dealkylation & keto reduction. In man ... acidic urine pH ... recoveries after oral dose of racemic diethylpropion ... n-ethylaminopropiophenone & norephedrine ca 25%, n-diethylnorephedrine & n-ethylnorephedrine ca 15%, diethylpropion & aminopropiophenone 2-3%.
The metabolism and urinary excretion of diethylpropion were re-evaluated using a newly developed gas chromatography procedure on urine samples obtained from 3 healthy volunteers who were given 25 mg diethylpropion hydrochloride in aqueous solution or 75 mg as a sustained-action preparation of diethylpropion. After an oral dose the metabolism of diethylpropion is rapid and extensive; only 3-4% remains unchanged. Mono-N-de-ethylation is the main metabolic pathway for about 35% of the dose. N-De-ethylation is more important than carbonyl reduction, occurring mainly with the unchanged diethylpropion, about 20% of the dose. About 30% of the dose, which cannot be accounted for as the sum of the amines recovered in urine, is probably metabolized by deamination, followed by oxidation and conjugation to give hippuric acid.
IDENTIFICATION: Diethylpropion hydrochloride is a centrally acting antiobesity drug. Indications: Appetite suppressant (anorectic) for benzphetamine, diethypropion, phendimetrazine, phenmetrazine and phentermine. Misuse: Performance enhancement and relief of fatigue. Abuse: Abuse either orally or by injection is extremely common. HUMAN EXPOSURE: Main risks and target organs: Acute central nervous system stimulation, cardiotoxicity causing tachycardia, arrhythmias, hypertension and cardiovascular collapse. High risk of dependency and abuse. Summary of clinical effects: Cardiovascular: Palpitation, chest pain, tachycardia, arrhythmias and hypertension are common; cardiovascular collapse can occur in severe poisoning. Myocardial ischemia, infarction and ventricular dysfunction are described. Central Nervous System (CNS): Stimulation of CNS, tremor, restlessness, agitation, insomnia, increased motor activity, headache, convulsions, coma and hyperreflexia are described. Stroke and cerebral vasculitis have been observed. Gastrointestinal: Vomiting, diarrhoea and cramps may occur. Acute transient ischemic colitis has occurred with chronic methamphetamine abuse. Genitourinary: Increased bladder sphincter tone may cause dysuria, hesitancy and acute urinary retention. Renal failure can occur secondary to dehydration or rhabdomyolysis. Renal ischemia may be noted. Dermatologic: Skin is usually pale and diaphoretic, but mucous membranes appear dry. Endocrine: Transient hyperthyroxinaemia may be noted. Metabolism: Increased metabolic and muscular activity may result in hyperventilation and hyperthermia. Weight loss is common with chronic use. Fluid/Electrolyte: Hypo- and hyperkalemia have been reported. Dehydration is common. Musculoskeletal: Fasciculations and rigidity may be noted. Rhabdomyolysis is an important consequence of severe amphetamine poisoning. Psychiatric: Agitation, confusion, mood elevation, increased wakefulness, talkativeness, irritability and panic attacks are typical. Chronic abuse can cause delusions and paranoia. A withdrawal syndrome occurs after abrupt cessation following chronic use. Contraindications: Anorexia, insomnia, psychopathic personality disorders, suicidal tendencies, Gilles de la Tourette syndrome and other disorders, hyperthyroidism, narrow angle glaucoma, diabetes mellitis and cardiovascular diseases such as angina, hypertension and arrythmias. Amphetamine interacts with several other drugs. Routes of exposure: Oral: Readily absorbed from the gastro-intestinal tract and buccal mucosa. It is resistant to metabolism by monoamine oxidase. Inhalation: Amphetamine is rapidly absorbed by inhalation and is abused by this route. Parenteral: Frequent route of entry in abuse situations. Absorption by route of exposure: Amphetamine is rapidly absorbed after oral ingestion. Peak plasma levels occur within 1 to 3 hours, varying with the degree of physical activity and the amount of food in the stomach. Absorption is usually complete by 4 to 6 hours. Sustained release preparations are available as resin-bound, rather than soluble, salts. These compounds display reduced peak blood levels compared with standard amphetamine preparations, but total amount absorbed and time to peak levels remain similar. Distribution by route of exposure: Amphetamines are concentrated in the kidney, lungs, cerebrospinal fluid and brain. They are highly lipid soluble and readily cross the blood-brain barrier. Protein binding and volume of distribution varies widely. Biological half-life by route of exposure: Under normal conditions, about 30% of amphetamine is excreted unchanged in the urine but this excretion is highly variable and is dependent on urinary pH. When the urinary pH is acidic (pH 5.5 to 6.0), elimination is predominantly by urinary excretion with approximately 60% of a dose of amphetamine being excreted unchanged by the kidney within 48 hours. When the urinary pH is alkaline (pH 7.5 to 8.0), elimination is predominantly by deamination (less than 7% excreted unchanged in the urine); the half-life ranging from 16 to 31 hours. Metabolism: The major metabolic pathway for amphetamine involves deamination by cytochrome P450 to para-hydroxyamphetamine and phenylacetone; this latter compound is subsequently oxidized to benzoic acid and excreted as glucuronide or glycine (hippuric acid) conjugate. Smaller amounts of amphetamine are converted to norephedrine by oxidation. Hydroxylation produces an active metabolite, O-hyroxynorephedrine, which acts as a false neurotransmitter and may account for some drug effect, especially in chronic users. Elimination and excretion: Normally 5 to 30% of a therapeutic dose of amphetamine is excreted unchanged in the urine by 24 hours, but the actual amount of urinary excretion and metabolism is highly pH dependent. Mode of action: Toxicodynamics: Amphetamine appears to exert most or all of its effect in the CNS by causing release of biogenic amines, especially norepinephrine and dopamine, from storage sites in nerve terminals. It may also slow down catecholamine metabolism by inhibiting monoamine oxidase. Adults: The toxic dose varies considerably due to individual variations and the development of tolerance. Children: Teratogenicity: The use of amphetamine for medical indications does not pose a significant risk to the fetus for congenital anomalies. Amphetamines generally do not appear to be human teratogens. Mild withdrawal symptoms may be observed in the newborn, but the few studies of infant follow-up have not shown long-term sequelae, although more studies of this nature are needed. Illicit maternal use or abuse of amphetamine presents a significant risk to the foetus and newborn, including intrauterine growth retardation, premature delivery and the potential for increased maternal, fetal and neonatal morbidity. These poor outcomes are probably multifactorial in origin, involving multiple drug use, life-styles and poor maternal health. However, cerebral injuries occurring in newborns exposed in utero appear to be directly related to the vasoconstrictive properties of amphetamines. Sixty-five children were followed whose mothers were addicted to amphetamine during pregnancy, at least during the first trimester. Intelligence, psychological function, growth, and physical health were all within the normal range at eight years, but those children exposed throughout pregnancy tended to be more aggressive. Interactions: Acetazolamide: administration may increase serum concentration of amphetamine. Alcohol: may increase serum concentration of amphetamine. Ascorbic acid: lowering urinary pH, may enhance amphetamine excretion Furazolidone: amphetamines may induce a hypertensive response in patients taking furazolidone. Guanethidine: amphetamine inhibits the antihypertensive response to guanethidine. Haloperidol: limited evidence indicates that haloperidol may inhibit the effects of amphetamine but the clinical importance of this interaction is not established. Lithium carbonate: isolated case reports indicate that lithium may inhibit the effects of amphetamine. Monoamine oxidase inhibitor: severe hypertensive reactions have followed the administration of amphetamines to patients taking monoamine oxidase inhibitors. Noradrenaline: amphetamine abuse may enhance the pressor response to noradrenaline. Phenothiazines: amphetamine may inhibit the antipsychotic effect of phenothiazines, and phenothiazines may inhibit the anorectic effect of amphetamines. Sodium bicarbonate: large doses of sodium bicarbonate inhibit the elimination of amphetamine, thus increasing the amphetamine effect. Tricyclic antidepressants: theoretically increases the effect of amphetamine, but clinical evidence is lacking. Acute poisoning: Ingestion: Effects are most marked on the central nervous system, cardiovascular system, and muscles. The triad of hyperactivity, hyperpyrexia, and hypertension is characteristic of acute amphetamine overdosage. Agitation, confusion, headache, delirium, and hallucination, can be followed by coma, intracranial hemorrhage, stroke, and death. Chest pain, palpitation, hypertension, tachycardia, atrial and ventricular arrhythmia, and myocardial infarction can occur. Muscle contraction, bruxism (jaw-grinding), trismus (jaw clenching), fasciculation, rhabdomyolysis, are seen leading to renal failure; and flushing, sweating, and hyperpyrexia can all occur. Hyperpyrexia can cause disseminated intravascular coagulation. Inhalation: The clinical effects are similar to those after ingestion, but occur more rapidly. Parenteral exposure: Intravenous injection is a common mode of administration of amphetamine by abusers. The euphoria produced is more intense. Other clinical effects are similar to those observed after ingestion, but occur more rapidly. Chronic poisoning: Ingestion: Tolerance to the euphoric effects and CNS stimulation induced by amphetamine develops rapidly, leading abusers to use larger and larger amounts to attain and sustain the desired affect. Habitual use or chronic abuse usually results in toxic psychosis classically characterised by paranoia, delusions and hallucinations, which are usually visual, tactile or olfactory in nature, in contrast to the typical auditory hallucinations of schizophrenia. The individual may act on the delusions, resulting in bizarre violent behaviour, hostility and aggression, sometimes leading to suicidal or homicidal actions. Dyskinesia, compulsive behaviour and impaired performance are common in chronic abusers. The chronic abuser presents as a restless, garrulous, tremulous individual who is suspicious and anxious. Mild toxicity: restlessness, irritability, insomnia, tremor, hyperreflexia, sweating, dilated pupils, flushing. Moderate toxicity: hyperactivity, confusion, hypertension, tachypnea, tachycardia, mild fever, sweating. Severe toxicity: delirium, mania, self-injury, marked hypertension, tachycardia, arrhythmia, hyperpyrexia, convulsion, coma, circulatory collapse. Death can be due to intracranial hemorrhage, acute heart failure or arrhythmia, hyperpyrexia, rhabdomyolysis and consequent hyperkalaemia or renal failure, and to violence related to the psychiatric effects. Cardiovascular: Cardiovascular symptoms of acute poisoning include palpitation and chest pain. Tachycardia and hypertension are common. Severe poisoning can cause acute myocardial ischemia, myocardial infarction, and left ventricular failure. These probably result from vasospasm, perhaps at sites of existing atherosclerosis. In at least one case, thrombus was demonstrated initially. Chronic oral amphetamine abuse can cause a chronic cardiomyopathy; an acute cardiomyopathy has also been described. Intra-arterial injection of amphetamine can cause severe burning pain, vasospasm, and gangrene. Respiratory: Pulmonary fibrosis, right ventricular hypertrophy and pulmonary hypertension are frequently found at post-mortem examination. Pulmonary function tests usually are normal except for the carbon monoxide diffusing capacity. Respiratory complications are sometimes caused by fillers or adulterants used in injections by chronic users. These can cause multiple microemboli to the lung, which can lead to restrictive lung disease. Pneumomediastinum has been reported after amphetamine inhalation. Neurological: Central nervous system (CNS): Main symptoms include agitation, confusion, delirium, hallucinations, dizziness, dyskinesia, hyperactivity, muscle fasciculation and rigidity, rigors, tics, tremors, seizures and coma. Both occlusive and haemorrhagic strokes have been reported after abuse of amphetamines. Twenty-one of 73 drug-using young persons with stroke had taken amphetamine, of whom six had documented intracerebral haemorrhage and two had subarachnoid haemorrhage. Patients with underlying arteriovenous malformations may be at particular risk. Stroke can occur after oral, intravenous, or nasal administration. Severe headache beginning within minutes of ingestion of amphetamine is usually the first symptom. In more than half the cases, hypertension which is sometimes extreme, accompanies other symptoms. A Cerebral vasculitis has also been observed. Dystonia and dyskinesia can occur, even with therapeutic dosages. Psychiatric effects, particularly euphoria and excitement, are the motives for abuse. Paranoia and a psychiatric syndrome indistinguishable from schizophrenia are sequelae of chronic use. Autonomic nervous system: Stimulation of alpha-adrenergic receptors produces mydriasis, increased metabolic rate, diaphoresis, increased sphincter tone, peripheral vasoconstriction and decreased gastrointestinal motility. Stimulation of beta-adrenergic receptors produces increased heart rate and contractility, increased automaticity and dilatation of bronchioles. Skeletal and smooth muscle: Myalgia, muscle tenderness, muscle contractions, and rhabdomyolysis, leading to fever, circulatory collapse, and myoglobinuric renal failure, can occur with amphetamines. Gastrointestinal: Most common symptoms are nausea, vomiting, diarrhea, and abdominal cramps. Anorexia may be severe. Epigastric pain and hematemesis have been described after intravenous amphetamine use. Hepatic: Hepatitis and fatal acute hepatic necrosis have been described. Urinary: Renal: Renal failure, secondary to dehydration or rhabdomyolysis may be observed. Other: Increased bladder sphincter tone may cause dysuria, hesitancy and acute urinary retention. This effect may be a direct result of peripheral alpha-agonist activity. Spontaneous rupture of the bladder has been described in a young woman who took alcohol and an amphetamine-containing diet tablet. Endocrine and reproductive systems: Transient hyperthyroxinaemia may result from heavy amphetamine use. Dermatological: Skin is usually pale and diaphoretic, but mucous membranes appear dry. Chronic users may display skin lesion, abscesses, ulcers, cellulitis or necrotising angiitis due to physical insult to skin, or dermatologic signs of dietary deficiencies, e.g. cheilosis, purpura. Eye, ear, nose, throat: local effects: Mydriasis may be noted. Diffuse hair loss may be noted. Chronic users may display signs of dietary deficiencies. Hematological: Disseminated intravascular coagulation is an important consequence of severe poisoning. Idiopathic thrombocytopenic purpura may occur. Immunological Breast-feeding: Amphetamine is passed into breast milk and measurable amounts can be detected in breast-fed infant's urine. Therefore lactating mothers are advised not to take or use amphetamine.
Diethylpropion is an amphetamine that stimulates neurons to release or maintain high levels of a particular group of neurotransmitters known as catecholamines; these include dopamine and norepinephrine. High levels of these catecholamines tend to suppress hunger signals and appetite. Diethylpropion (through catecholamine elevation) may also indirectly affect leptin levels in the brain. It is theorized that diethylpropion can raise levels of leptin which signal satiety. It is also theorized that increased levels of the catecholamines are partially responsible for halting another chemical messenger known as neuropeptide Y. This peptide initiates eating, decreases energy expenditure, and increases fat storage.
Diethylpropion has not been linked to an increased rate of serum enzyme elevations during therapy; however, actual results of ALT monitoring during diethylpropion therapy have rarely been reported. Despite long term availability and wide use of diethylpropion, there have been no published reports linking it to clinically apparent acute liver injury.
Diethylpropion is rapidly absorbed from the GI tract after oral administration and is extensively metabolized through a complex pathway of biotransformation involving N-dealkylation and reduction. Diethylpropion and/or its active metabolites are believed to cross the blood-brain barrier and the placenta. Diethylpropion and its metabolites are excreted mainly by the kidney.
来源:DrugBank
吸收、分配和排泄
Diethylpropion从胃肠道吸收良好，口服常规片剂后其效果可持续约4小时。
Diethylpropion is readily absorbed from the GI tract and its effects persist for about 4 hours after oral administration of conventional tablets.
[EN] IMIDAZOLE DERIVATIVES USEFUL AS INHIBITORS OF FAAH<br/>[FR] DÉRIVÉS IMIDAZOLE UTILES COMME INHIBITEURS DE LA FAAH
申请人：MERCK & CO INC
公开号：WO2009152025A1
公开（公告）日：2009-12-17
The present invention is directed to certain imidazole derivatives which are useful as inhibitors of Fatty Acid Amide Hydrolase (FAAH). The invention is also concerned with pharmaceutical formulations comprising these compounds as active ingredients and the use of the compounds and their formulations in the treatment of certain disorders, including osteoarthritis, rheumatoid arthritis, diabetic neuropathy, postherpetic neuralgia, skeletomuscular pain, and fibromyalgia, as well as acute pain, migraine, sleep disorder, Alzeimer Disease, and Parkinson's Disease.
[EN] PYRAZOLE DERIVATIVES USEFUL AS INHIBITORS OF FAAH<br/>[FR] DÉRIVÉS DE PYRAZOLE UTILES COMME INHIBITEURS DE FAAH
申请人：MERCK & CO INC
公开号：WO2009151991A1
公开（公告）日：2009-12-17
The present invention is directed to certain imidazole derivatives which are useful as inhibitors of Fatty Acid Amide Hydrolase (FAAH). The invention is also concerned with pharmaceutical formulations comprising these compounds as active ingredients and the use of the compounds and their formulations in the treatment of certain disorders, including osteoarthritis, rheumatoid arthritis, diabetic neuropathy, postherpetic neuralgia, skeletomuscular pain, and fibromyalgia, as well as acute pain, migraine, sleep disorder, Alzheimer disease, and Parkinson's disease
[EN] OXAZOLE DERIVATIVES USEFUL AS INHIBITORS OF FAAH<br/>[FR] DÉRIVÉS D'OXAZOLE UTILES COMME INHIBITEURS DE FAAH
申请人：MERCK & CO INC
公开号：WO2010017079A1
公开（公告）日：2010-02-11
The present invention is directed to certain oxazole derivatives which are useful as inhibitors of Fatty Acid Amide Hydrolase (FAAH). The invention is also concerned with pharmaceutical formulations comprising these compounds as active ingredients and the use of the compounds and their formulations in the treatment of certain disorders, including osteoarthritis, rheumatoid arthritis, diabetic neuropathy, postherpetic neuralgia, skeletomuscular pain, and fibromyalgia, as well as acute pain, migraine, sleep disorder, Alzeimer Disease, and Parkinson's Disease.
[EN] HETEROCYCLIC COMPOUNDS FOR THE TREATMENT OF STRESS-RELATED CONDITIONS<br/>[FR] COMPOSÉS HÉTÉROCYCLIQUES POUR LE TRAITEMENT D'ÉTATS LIÉS AU STRESS
申请人：OTSUKA PHARMA CO LTD
公开号：WO2010137738A1
公开（公告）日：2010-12-02
The present invention provides a novel heterocyclic compound. A heterocyclic compound represented by general formula (1) wherein, R1 and R2, each independently represent hydrogen; a phenyl lower alkyl group that may have a substituent(s) selected from the group consisting of a lower alkyl group and the like on a benzene ring and/or a lower alkyl group; or a cyclo C3-C8 alkyl lower alkyl group; or the like; R3 represents a lower alkynyl group or the like; R4 represents a phenyl group that may have a substituent(s) selected from the group consisting of a 1,3,4-oxadiazolyl group that may have e.g., halogen or a heterocyclic group selected from pyridyl group and the like; the heterocyclic group may have at least one substituent(s) selected from a lower alkoxy group and the like or a salt thereof.
[EN] METHYL OXAZOLE OREXIN RECEPTOR ANTAGONISTS<br/>[FR] MÉTHYLOXAZOLES ANTAGONISTES DU RÉCEPTEUR DE L'OREXINE
申请人：MERCK SHARP & DOHME
公开号：WO2016089721A1
公开（公告）日：2016-06-09
The present invention is directed to methyl oxazole compounds which are antagonists of orexin receptors. The present invention is also directed to uses of the compounds described herein in the potential treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The present invention is also directed to compositions comprising these compounds. The present invention is also directed to uses of these compositions in the potential prevention or treatment of such diseases in which orexin receptors are involved.
