Phentermine undergoes minimal p-hydroxylation, N-oxidation and N-hydroxylation followed by conjugation. The total proportion of the drug that goes under metabolism only represents about 6% of the administered dose where about 5% is represented by the N-oxidized and N-Hydroxylated metabolites.
来源:DrugBank
代谢
Phentermine is not significantly biotransformed; 70 to 80 % of a given dose is excreted unchanged in the urine.
菲尼特米不会显著生物转化；给定剂量的70到80%以原形从尿液中排出。
Phentermine is not significantly biotransformed; 70 to 80 % of a given dose is excreted unchanged in the urine.
There are two primary pathways of oxidative metabolism: n-hydroxylation to n-hydroxyphentermine & p-hydroxylation to para-hydroxyphentermine. N-hydroxyphentermine is metabolized further to alpha-nitrophentermine. In rats the dominant pathway is p-hydroxylation to give para-hydroxyphentermine, accounting for more than 60% of administered dose. P-hydroxylation reactions in rat liver microsomes indicated that phentermine metabolism was inhibited by skf525a & iprindol, and was not inducible with phenobarbital or 3-methylcholanthrene, suggesting a system different from aromatic c-hydroxylation. The n-hydroxylation reaction for rabbit & guinea pig (two-enzyme system) & rat (single enzyme system) is the reduced form of nicotinamide-adenine dinucleotide phosphate-dependent, inhibited by carbon monoxide & induced by phenobarbital, suggesting involvement of cytochrome p450 system.
Although no quantitative data are available, urinary metabolites found in man are p-hydroxyphentermine and n-hydroxyphentermine. N-hydroxy metabolite can be reduced in vivo but conversion to this metabolite appears to be inefficient means of elimination.
The role of the cytochrome p450 system in the oxidation of phentermine to N-hydroxyphentermine by liver microsomal prepn was studied in a reconstituted system which consisted of cytochrome p450 and the reduced form of nicotinamide-adenine dinucleotide phosphate cytochrome p450 reductase purified from liver microsomes of phenobarbital-induced rabbits. In this system, phentermine was oxidized to N-hydroxyphentermine. The reaction was the reduced form of nicotinamide-adenine dinucleotide phosphate-dependent and required the presence of both the cytochrome p450 and reductase preparations.
IDENTIFICATION: Phentermine hydrochloride is an amphetamine type antiobesity drug. Description: Indications: Used as an appetite suppressant (anorectic). 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, diarrhea and cramps may occur. Acute transient ischemic colitis has occurred with chronic abuse. Genitourinary: Increased bladder sphincter tone may cause dysuria, hesitancy and acute urinary retention. Renal failure can result secondary to dehydration or rhabdomyolysis. Renal ischemia may be noted. Dermatologic: Skin is usually pale and diaphoretic, but mucous membranes appear dry. Endocrine: Transient hyperthyroxinemia 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 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, Tourette syndrome and other disorders, hyperthyroidism, narrow angle glaucoma, diabetes mellitis and cardiovascular diseases such as angina, hypertension and arrhythmias. 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: Rapidly absorbed by inhalation and is abused by this route. Parenteral: Frequent route of entry in abuse situations. Absorption by route of exposure: 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 preparations, but total amount absorbed and time to peak levels remain similar. Distribution by route of exposure: 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% 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 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 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 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 is excreted unchanged in the urine by 24 hours, but the actual amount of urinary excretion and metabolism is highly pH dependent. Human data: Adults: The toxic dose varies considerably due to individual variations and the development of tolerance. Children: Children appear to be more susceptible than adults and are less likely to have developed tolerance. Teratogenicity: 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 presents a significant risk to the fetus 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. 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. Alcohol: may increase serum concentration. Ascorbic acid: lowering urinary pH, may enhance excretion. Furazolidone: May induce a hypertensive response in patients taking furazolidone. Guanethidine: This drug inhibits the antihypertensive response to guanethidine. Haloperidol: limited evidence indicates that haloperidol may inhibit the effects but the clinical importance of this interaction is not established. Lithium carbonate: isolated case reports indicate that lithium may inhibit the effects. Monoamine oxidase inhibitor: severe hypertensive reactions have followed the administration to patients taking monoamine oxidase inhibitors. Noradrenaline: Abuse may enhance the pressor response to noradrenaline. Phenothiazines: May inhibit the antipsychotic effect of phenothiazines, and phenothiazines may inhibit the anorectic effect. Sodium bicarbonate: large doses of sodium bicarbonate inhibit the elimination, thus increasing the effect. Tricyclic antidepressants: theoretically increases the effect, but clinical evidence is lacking. Clinical effects: 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 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 by abusers. The euphoria produced is more intense, leading to a rush or flash which is compared to sexual orgasm. 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 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 characterized 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 behavior, hostility and aggression, sometimes leading to suicidal or homicidal actions. Dyskinesia, compulsive behavior and impaired performance are common in chronic abusers. The chronic abuser presents as a restless, garrulous, tremulous individual who is suspicious and anxious. Course, prognosis, cause of death: Symptoms and signs give a clinical guide to the severity of intoxication as follows: 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 hyperkalemia or renal failure, and to violence related to the psychiatric effects. Systematic description of clinical effects: Cardiovascular: Cardiovascular symptoms of acute poisoning include palpitation and chest pain. Tachycardia and hypertension are common. One third of patients reported had a blood pressure greater than 140/90 mmHg, and nearly two-thirds had a pulse rate above 100 beats per minute. 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. Hypertensive stroke is a well-recognized complication of poisoning. Intra-arterial injection 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 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 hemorrhagic strokes have been reported after abuse.. Twenty-one of 73 drug-using young persons with stroke had taken amphetamine. A study found six individuals had documented intracerebral hemorrhage and two had subarachnoid hemorrhage. 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 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 ß-adrenergic receptors produces increased heart rate and contractility, increased automaticity and dilatation of bronchioles. Gastrointestinal: Most common symptoms are nausea, vomiting, diarrhea, and abdominal cramps. Anorexia may be severe. Epigastric pain and hematemesis have been described after intravenous use. A case of ischemic colitis with normal mesenteric arteriography in a patient taking dexamphetamine has been described. 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 hyperthyroxinemia may result from heavy use. Dermatological: Skin is usually pale and diaphoretic, but mucous membranes appear dry. Chronic users may display skin lesion, abscesses, ulcers, cellulitis or necrotizing angiitis due to physical insult to skin, or dermatologic signs of dietary deficiencies such as cheilosis and 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. Fluid and electrolyte disturbance: Increase metabolic and muscular activity may result in dehydration. Special risks: Pregnancy: Intelligence, psychological function, growth, and physical health were all within the normal range at eight years, but those exposed throughout pregnancy tended to be more aggressive. A case report describes a normal female infant born to mother who took dexamphetamine for narcolepsy throughout pregnancy. 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 these drugs. /Phentermine hydrochloride/
Phentermine 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. The drug seems to inhibit reuptake of noradrenaline, dopamine, and seratonin through inhibition or reversal of the reuptake transporters. It may also inhibit MAO enzymes leaving more neurotransmitter available at the synapse.Phentermine (through catecholamine elevation) may also indirectly affect leptin levels in the brain. It is theorized that phentermine 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.
Phentermine has not been linked to an increased rate of serum enzyme elevations during therapy; however, results of ALT monitoring during phentermine therapy have rarely been reported. Despite long term availability and wide use of phentermine, there have been no published reports linking it to clinically apparent acute liver injury.
Likelihood score: E (unlikely cause of clinically apparent liver injury).
Drug Class: Weight Loss Agents, see also Phentermine-Topiramate
Phentermine shows a dose-dependent pharmacokinetic profile. After oral administration of a dose of 15 mg, the maximal concentration was achieved after 6 hours and its bioavailability was not affected by the consumption of high-fat meals. The reported plasma concentration at steady-state is of around 200 ng/ml as observed in clinical trials.
来源:DrugBank
吸收、分配和排泄
消除途径
Phentermine主要通过尿液排泄，其中大约70-80%的给药剂量可以以原药形式找到。
Phentermine is excreted mainly in the urine from which about 70-80% of the administered dose can be found as the unchanged drug.
来源:DrugBank
吸收、分配和排泄
分布容积
据报道，芬特明的分布体积为5 L/kg。
The reported volume of distribution for phentermine is reported to be of 5 L/kg.
来源:DrugBank
吸收、分配和排泄
清除
经口服给药后的报告清除率为8.79 L/h，这一数据来自药代动力学的人群研究。
The reported clearance when administered orally is 8.79 L/h as observed in pharmacokinetic population studies.
来源:DrugBank
吸收、分配和排泄
经口服给药后易于吸收。广泛分布于全身。
Absorbed readily after oral administration. Distributed widely throughout body.
[EN] ACC INHIBITORS AND USES THEREOF<br/>[FR] INHIBITEURS DE L'ACC ET UTILISATIONS ASSOCIÉES
申请人：GILEAD APOLLO LLC
公开号：WO2017075056A1
公开（公告）日：2017-05-04
The present invention provides compounds I and II useful as inhibitors of Acetyl CoA Carboxylase (ACC), compositions thereof, and methods of using the same.
[EN] AZA PYRIDONE ANALOGS USEFUL AS MELANIN CONCENTRATING HORMONE RECEPTOR-1 ANTAGONISTS<br/>[FR] ANALOGUES D'AZAPYRIDONE UTILES COMME ANTAGONISTES DU RÉCEPTEUR 1 DE L'HORMONE CONCENTRANT LA MÉLANINE
申请人：BRISTOL MYERS SQUIBB CO
公开号：WO2010104818A1
公开（公告）日：2010-09-16
MCHR1 antagonists are provided having the following Formula (I): A1 and A2 are independently C or N; E is C or N; Q1, Q2, and Q3 are independently C or N provided that at least one of Q1, Q2, and Q3 is N but not more than one of Q1, Q2, and Q3 is N; D1 is a bond, -CR8R9 X-, -XCR8R9-, -CHR8CHR9-, -CR10=CR10'-, -C≡C-, or 1,2-cyclopropyl; X is O, S or NR11; R1, R2, and R3 are independently selected from the group consisting of hydrogen, halogen, lower alkyl, lower cycloalkyl, -CF3, -OCF3, -OR12 and -SR12; G is O, S or -NR15; D2 is lower alkyl, lower cycloalkyl, lower alkylcycloalkyl, lower cycloalkylalkyl, lower cycloalkoxyalkyl or lower alkylcycloalkoxy or when G is NR15, G and D2 together may optionally form an azetidine, pyrrolidine or piperidine ring; Z1 and Z2 are independently hydrogen, lower alkyl, lower cycloalkyl, lower alkoxy, lower cycloalkoxy, halo, -CF3, -OCONR14R14', -CN, -CONR14R14', -SOR12, -SO2R12, -NR14COR14', -NR14CO2R14', -CO2R12, NR14SO2R12 or COR12; R5, R6, and R7 are independently selected from the group consisting of hydrogen lower alkyl, lower cycloalkyl, -CF3, -SR12, lower alkoxy, lower cycloalkoxy, -CN, -CONR14R14', SOR12, SO2R12, NR14COR14', NR14CO2R12, CO2R12, NR14SO2R12 and -COR12; R8, R9, R10, R10', R11 are independently hydrogen or lower alkyl; R12 is lower alkyl or lower cycloalkyl; R14 and R14' are independently H, lower alkyl, lower cycloalkyl or R14 and R14' together with the N to which they are attached form a ring having 4 to 7 atoms; and R15 is independently selected from the group consisting of hydrogen and lower alkyl. Such compounds are useful for the treatment of MCHR1 mediated diseases, such as obesity, diabetes, IBD, depression, and anxiety.
[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.
