Moclobemide is almost completely metabolized in the liver by Cytochrome P450 2C19 and 2D6. Moclobemide is a substrate of CYP2C19. Although it acts as an inhibitor of CYP1A2, CYP2C19, and CYP2D6.
来源:DrugBank
代谢
甲氧卞氨酯在15名健康受试者（年龄23-27岁）中的代谢受到了甲琥脱氢酶氧化多态性的影响，其中包括7名甲琥脱氢酶的慢代谢者和8名快代谢者，他们接受了单次300毫克甲氧卞氨酯和多剂量的每日600毫克甲氧卞氨酯。甲琥脱氢酶的慢代谢者甲氧卞氨酯的清除率较低（单次剂量的中位数为16.1 vs 43.2 L/小时）且半衰期较长（单次剂量的中位数为4 vs 1.8小时），与快代谢者相比。通过C-羟基化形成的代谢物在慢代谢者中的血浆水平较低。因此，甲氧卞氨酯部分通过多态性的CYP2C19进行氧化代谢。代谢指标的变化与通过CYP2C19、CYP2D6和CYP1A2的氧化可逆性抑制相一致。结论是，甲氧卞氨酯的清除率与甲琥脱氢酶氧化多态性之间存在共分离现象。
The role of mephenytoin oxidation polymorphism in the metabolism of moclobemide was studied in 15 healthy subjects (ages 23-27 yr), including 7 poor metabolizers and 8 extensive metabolizers of S-mephenytoin, who received a single dose of 300 mg moclobemide and multiple doses of 600 mg/day moclobemide. Poor metabolizers of S-mephenytoin had lower moclobemide clearance (median single dose 16.1 vs 43.2 L/hr) and longer half-life (median single dose 4 vs 1.8 hr) compared with extensive metabolizers. Plasma levels of a metabolite formed by C-hydroxylation were lower in poor metabolizers. Moclobemide thus partially underwent oxidative metabolism via polymorphic CYP2C19. Changes in metabolic indexes were compatible with reversible inhibition of oxidation by way of CYP2C19, CYP2D6, and CYP1A2. It was concluded that there is a cosegregation between moclobemide clearance and mephenytoin oxidation polymorphism.
来源:Hazardous Substances Data Bank (HSDB)
代谢
Moclobemide appears to be eliminated (after first-pass hepatic metabolism) by first-order kinetics, resulting in urinary excretion of the monoamine metabolites homovanillic acid (HAV), dihydroxyphenylacetic acid (DOPAC), 3-methoxy-4-hydroxy-phenyl glycol (DOPEG), and 5-hydroxyindoleacetic acid (5-HIAA).
莫氯苯咪唑在首次通过肝脏代谢后，似乎以一级动力学被消除，导致尿液排出单胺类代谢物，包括同型香草酸（HAV）、二羟基苯乙酸（DOPAC）、3-甲氧基-4-羟基-苯乙二醇（DOPEG）和5-羟基吲哚乙酸（5-HIAA）。
Moclobemide appears to be eliminated (after first-pass hepatic metabolism) by first-order kinetics, resulting in urinary excretion of the monoamine metabolites homovanillic acid (HAV), dihydroxyphenylacetic acid (DOPAC), 3-methoxy-4-hydroxy-phenyl glycol (DOPEG), and 5-hydroxyindoleacetic acid (5-HIAA).
Moclobemide is almost completely metabolized in the liver by Cytochrome P450 2C19 and 2D6.
Half Life: 1-2 hours (4 hours in cirrhotic patients); metabolites are renally excreted
IDENTIFICATION: Moclobemide is a monoamine oxidase inhibitor drug. Moclobemide is a white to red crystalline substance with a weak odor. It is soluble in chloroform, methanol and water. Indications: Accepted: Major mental depression and dysthymia. Investigational: Menopausal flushing, prophylactic treatment of migraine, smoking cessation and abstinence in heavy dependent smokers. HUMAN EXPOSURE: Main risks and target organs: Moclobemide is a short-acting, selective and reversible monoamine oxidase type A inhibitor (MAO-AI). It is generally well tolerated in overdose when taken alone. The serotonergic effects of moclobemide may be enhanced by combination with tricyclic antidepressants, other monoamine oxidase inhibitors, selective serotonin reuptake inhibitors (SSRIs), lithium or serotonergic substances. A life-threatening serotonin syndrome consisting of hyperthermia, tremor and convulsions can develop when moclobemide is ingested with these drugs. The concomitant consumption of large amounts of tyramine-rich foodstuff may result in a moderate increase of systolic blood pressure (cheese reaction). Summary of clinical effects: Agitation, drowsiness, disorientation, slow-reacting pupils, myoclonic jerks in upper extremities; hypo or Hypertension, tachycardia; nausea, vomiting, abdominal pain. Contraindications: Absolute: Hypersensitivity to moclobemide, children less than 15 years old, breast feeding (in the absence of available data on potential toxic effects to suckling infants): less than 3 % of the administered dose of moclobemide is excreted in breast milk. Coadministration of sumatriptan: hypertensive crises, severe coronary vasoconstriction may occur. Co-administration of pethidine (meperidine), dextromethorphan: the serotonin syndrome may occur. Moclobemide is contraindicated in patients with acute confusional states and in those with pheochromocytoma. It should be avoided in excited or agitated patients and in those with severe hepatic impairment. Relative: Co-administration of drugs which increase the levels of monoamines such as serotonin and norepinephrine: tricyclic antidepressants, selective serotonin re-uptake inhibitor antidepressants: a serotonin syndrome may occur. Alcohol (as for other psychoactive drugs). Routes of exposure: Oral: Moclobemide is available as tablets, thus ingestion is the most common route of exposure. Kinetics: Absorption by route of exposure: Readily absorbed from the gastro-intestinal tract. Food delays absorption. Peak plasma concentration: 1 to 2 hours after ingestion. Oral bioavailability was reported as 60 % after a single dose and 80 % after repeated doses, due to an important and saturable hepatic first-pass effect. Distribution by route of exposure: Widely distributed throughout the body. Plasma protein binding is 50 %. After oral administration to 6 healthy subjects, the mean volume of distribution was about 1 L/kg. Biological half-life by route of exposure: After single oral doses, plasma half-life is 1 to 2 hours; with long term treatment, the half-life is reported to increase to 2 to 4 hours. Metabolism: Moclobemide undergoes extensive metabolism, mainly carbon and nitrogen oxidation in the liver, deamination and aromatic hydroxylation. Metabolites are inactive. Elimination and excretion: Metabolites of moclobemide and a small amount of unchanged drug (less than 1 %) are excreted in the urine; after an oral dose of radio-labelled moclobemide, 92% of the dose was excreted in the urine within 12 hours.Mode of action: Toxicodynamics: Moclobemide selectively and reversibly inhibits the activity of the intracellular enzyme monoamine oxidase A (MAO-A), thus preventing the normal metabolism of biogenic amines (noradrenaline, adrenaline, serotonin, dopamine). Mono amine oxidase inhibitors (MAOIs) exert their toxic effects by inhibiting the metabolism of sympathomimetic amines and serotonin, and by decreasing noradrenaline stores in post-ganglionic sympathetic neurons. They do not inhibit MAO synthesis. MAOIs also inhibit enzymes other than MAO, including dopamine-beta-oxidase, diamine-oxidase, amino-acid decarboxylase and choline dehydrogenase. Inhibition of these enzymes occurs only with very high doses of MAOIs and may be responsible for some of the toxic effects of MAOIs. Drugs that enhance serotonin release or reuptake (tricyclic antidepressants, selective serotonin reuptake inhibitors) may cause the serotonin syndrome when they are administered concurrently with the MAOIs, even at therapeutic doses. A toxic reaction to MAOIs may be caused by pressor amines such as tyramine, resulting in hypertensive crisis. When the protective role of intestinal and hepatic MAO is eliminated, increased absorption of tyramine from certain foods occurs and can cause a significant increase in blood pressure (cheese reaction) through the release of noradrenaline from pre-synaptic vesicles. Two isoforms of the MAO enzyme have been discovered: MAO-A and MAO-B. These isoforms differ in anatomical distribution and preferred substrates. The new MAOIs such as moclobemide are isoform selective and reversibly inhibit MAO-A. Thus having a lower potential for interactions than non selective MAOIs at therapeutic doses. Selectivity is lost in overdoses and in extreme situations such as high-dose combination therapies and mixed drug overdoses, and severe toxic reactions may occur. Pharmacodynamics: The MAOs are a group of enzymes that metabolize, and therefore inactivate endogenous pressor amines (such as norepinephrine, dopamine, serotonin) as well as ingested indogenous amines (such as tyramine). MAOIs inhibit the degradation of these amines by MAO. The increased availability of biogenic amines (such as norepinephrine and serotonin) is thought to be linked with the improvement in depression accounted for by MAIO treatment. Two isoforms of the MAO enzyme have been discovered: MAO-A and MAO-B, which differ in anatomical distribution and preferred substrates. The MAO type A enzymes preferentially metabolize serotonin and noradrenaline and are located primarily in the placenta, gut and liver. The MAO type B enzymes are predominant in brain, liver and platelets, and phenylethylamine, methylhistamine and tryptamine are their primary substrates. Both MAO-A and MAO-B metabolize tyramine. New MAOIs such as moclobemide, which are isoform selective and have reversible inhibition of the enzyme are called Reversible Inhibitors of MAO-A. The duration of MAO-A inhibition by moclobemide is shorter (16 to 24 hours) than the inhibition induced by conventional MAOIs (> 10 days). The interaction of the newer MAO-AI with hepatic cytochrome P450 appears to be much weaker than with the irreversible and nonspecific MAOIs. However, several studies in humans have suggested there is some involvement of cytochtome P450 in the metabolism of moclobemide, and also a weak inhibitory effect of moclobemide for its isoenzyme CYP2D6. The clinical relevance of this weak interaction is not clear and is probably of little consequence. Like tricyclic antidepressants, SSRIs and other MAOIs, moclobemide significantly reduces REM (rapid eye movement) sleep density, REM time and the REM percentage of total sleep time in patients with major depression. Interactions: Drug-food interactions: the dietary restrictions that need to be followed with irreversible MAOIs are less stringent with selective reversible inhibitors of monoamine oxidase type A such as moclobemide. However, the manufacturer of moclobemide recommends that since some patients may be more sensitive to tyramine, the consumption of large amounts of tyramine-rich foodstuffs should still be avoided; these foods include chocolate, aged cheeses, beer, chianti, vermouth, pickled fish and concentrated yeast extracts. Drug-drug interactions: Sympathomimetics and anorectic drugs should not be taken with moclobemide. Opioid analgesics: Central Nervous System (CNS) excitation or depression may occur. Drugs used in anesthesia: anesthesia may be performed 24 hours after discontinuation of moclobemide with little potential for significant interaction; when the washout period is not feasible, the use of meperidine and parenteral sympathomimetics should be avoided. Levodopa: a hypertensive crisis may be precipitated. Sumatriptan: the manufacturer recommends to not prescribe moclobemide concominantiantly with sumatriptan which is a selective agonist at serotonin type 1D receptors, because of possible hypertensive crises and severe coronary vasoconstriction, and advises a washout period of 24 hours after discontinuation of moclobemide; however a clinical study involving 103 episodes of migraine, did not show evidence of significant adverse effects. The metabolism of moclobemide is inhibited by cimetidine, leading to a prolonged half-life and increased plasma concentrations; the manufacturer recommends that the dose of moclobemide be reduced to half strength in patients who are also given cimetidine. The co-administration of drugs that increase the levels of monoamines such as serotonin and norepinephrine, including tricyclic antidepressants (mainly clomipramine), selective serotonin re-uptake inhibitor antidepressants, and potentially other antidepressants may cause a serotonin syndrome. Lithium: Care should be taken when co-prescribing MAO-AI with lithium, since it increases serotonin levels, although no interactions have been reported to date. Therapy with moclobemide should not be started until at least 7 days following the discontinuation of tricyclic or serotonin reuptake inhibitor antidepressant treatment (2 weeks in the case of paroxetine; 5 weeks in the case of fluoxetine) or for at least a week after stopping treatment with other monoamine oxidase inhibitors. Conversely, a washout period of 24 hours is advised when switching from moclobemide to other antidepressants. Antipsychotics, benzodiazepines, nifedipine and hydrochlorothiazide may be coprescribed without major interaction. Main adverse effects: They include sleep disturbances, dizziness, nausea, and headache. Confusional states, restlessness or agitation may occur. Mild elevations in liver enzyme values have been reported. Care is required in patients with thyrotoxicosis as moclobemide may theoretically precipitate a hypertensive reaction. Mental alertness may be impaired, patients under treatment should not drive or operate machinery. Manic episodes may be provoked in patients with bipolar disorders, moclobemide should be discontinued and antipsychotic therapy should be initiated. Less common adverse effects include: hypertension, although the role of concomitant administration of clomipramine, buspirone, and thyroxin in the case series reported may have contributed and cannot be disregarded, alopecia. Acute poisoning: Ingestion: Patients may display minimal or no symptoms following pure moclobemide overdose. However, the ingestion of moclobemide may cause nausea, vomiting, gastric pain; agitation, disorientation, drowsiness, impaired reflexes, myoclonic jerks in upper extremities, slow reacting pupils; slight rise in blood pressure or moderate hypotension and tachycardia. Co-ingestion of tricyclic antidepressants (primarily clomipramine), opioids, or selective serotonin reuptake inibitors can result in more varied and severe symptoms appearing within 2 to 3 hours after ingestion, even with lower doses of moclobemide. Symptoms include: both CNS depression (confusion, drowsiness) and excitation (seizure), tremor, mydriasis, hyperthermia with muscle rigidity, hypertension and metabolic acidosis. Several fatal cases have been reported after a combination of moclobemide with citalopram, clomipramine and fluoxetine and moclobemide with citalopram and fluoxetine. Course, prognosis, cause of death: Pure moclobemide overdoses usually have a fairly benign course. Several fatalities are reported in the literature, all involving a co-ingestion. The clinical course consisted of euphoria, agitation, then extreme tremor, followed by convulsions and hyperthermia. Death occurred within 3 to 16 hours after ingestion, after intractable seizure and/or hyperthermia and its subsequent complications: disseminated intravascular coagulation and multiple organ failure. Systematic description of clinical effects: Cardiovascular: Mild to moderate hypertension, moderate hypotension and sinus tachycardia. Neurological: Central nervous system: Mild disorientation, agitation, slurred speech, anxiety, dizziness; headache; drowsiness, coma. Autonomic nervous system: Slow-reacting pupils, mydriasis. Skeletal and smooth muscle: Myoclonic jerks in upper extremities; muscle rigidity; rhabdomyolysis. Gastrointestinal: Dry mouth; nausea, vomiting, gastric pain; diarrhea. Hepatic: Mild increases in liver enzymes values. Urinary: Renal Metabolic: Acid-base disturbances: Acidosis is expected in association with coma and/or convulsions. Fluid and electrolyte disturbances: Hyperkalemia. Others: Creatine phosphokinase may be elevated in patients with muscular hyperactivity or rigidity. ANIMAL STUDIES: In mice: (after oral and ip injection) Symptomatology: sedation, muscle twitching, respiratory depression, death. In rats: (after oral and ip injection) Symptomatology: sedation, respiratory depression, death. In rabbits (after oral and ip injection): Symptomatology: ataxia, decrease in motor activity, respiratory depression, tremor, seizures, salivation and death. Carcinogenicity: Animal studies: moclobemide was not carcinogenic in rats at oral doses for 2 years. In mice given the drug orally over 80 weeks, no carcinogenic effect was observed. Teratogenicity: Animal studies: doses up to 100 mg/kg/day did not affect fertility in rats. In rabbits and rats oral doses of up to 100 and 200 mg/kg/day respectively did not have embryotoxic or teratogenic effects. Mutagenicity: In vitro and in vivo: moclobemide did not show mutagenicity.
The mechanism of action of moclobemide involves the selective, reversible inhibition of MAO-A. This inhibition leads to a decrease in the metabolism and destruction of monoamines in the neurotransmitters. This results in an increase in the monoamines, relieving depressive symptoms.
来源:Toxin and Toxin Target Database (T3DB)
毒理性
致癌物分类
对人类不具有致癌性（未被国际癌症研究机构IARC列名）。
No indication of carcinogenicity to humans (not listed by IARC).
◉ Summary of Use during Lactation:Moclobemide is not approved for marketing in the United States by the U.S. Food and Drug Administration, but is available in other countries. Limited information indicates that maternal doses of moclobemide up to 900 mg daily produce low levels in milk. Although several breastfed infants apparently experienced no adverse effects during maternal use of moclobemide, no rigorous, long-term data are available. Until more data are available, moclobemide should only be used with careful monitoring during breastfeeding, especially while nursing a newborn or preterm infant.
◉ Effects in Breastfed Infants:Nine women were being treated for postpartum depression with moclobemide in daily dosages ranging from 150 mg to 900 mg. All breastfed (extent not stated) their infants during therapy, but the duration of infant exposure to moclobemide in breastmilk was not stated. Maternal reports of infant weight gain, milestones and behavioral effects as well as clinical observation by the authors indicted no adverse effects in the breastfed infants.
Four women who took moclobemide in dosages of 300 mg to 1200 mg daily during pregnancy were followed up in the neonatal period and at 1 year postpartum. All women breastfed (extent not stated) their infants. One woman ceased breastfeeding at 2 months postpartum because of severe gastroesophageal reflux in the infant; two other mothers breastfed beyond 12 months. The duration of breastfeeding in the fourth infant was not sated. All infants achieved developmental milestones.
◉ Effects on Lactation and Breastmilk:Moclobemide increases serum prolactin in males and has caused galactorrhea in women. The prolactin level in a mother with established lactation may not affect her ability to breastfeed.
Well absorbed from the gastrointestinal tract (> 95%). The presence of food reduces the rate but not the extent of absorption. Hepatic first pass metabolism reduces bioavailability to 45-70% following administration of a single dose, but increases to 80% with multiple dosing as a result of saturation of the first pass effect. Peak plasma concentrations are reached within 1 - 2 hours following oral administration.
Well absorbed from the gastrointestinal tract (> 95%). The presence of food reduces the rate but not the extent of absorption. Hepatic first-pass metabolism reduces bioavailability to about 56% following administration of one dose, but increases to 90% with steady-state dosing as a result of saturation of the first pass effect. Peak plasma concentrations are reached within 0.3 - 1 hours following oral administration with a terminal half-life of 1.6h.
来源:DrugBank
吸收、分配和排泄
消除途径
莫氯苯咪唑几乎完全通过肾脏排泄。
Moclobemide is almost completely renally excreted.
Moclobemide is readily absorbed (>95%) through the gastrointestinal tract. Within 1 to 2 hours of oral use, a peak plasma level of about 1 ug/mL is reached. It is protein bound to the extent of 50%.
[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.
Heterobicyclic compounds of Formula (I):
or a pharmaceutically-acceptable salt, tautomer, or stereoisomer thereof, as defined in the specification, and compositions containing them, and processes for preparing such compounds. Provided herein also are methods of treating disorders or diseases treatable by inhibition of PDE10, such as obesity, non-insulin dependent diabetes, schizophrenia, bipolar disorder, obsessive-compulsive disorder, Huntington's Disease, and the like.
Formula (I)的杂环化合物：
或其药用可接受的盐、互变异构体或立体异构体，如规范中所定义，并含有它们的组合物，以及制备这种化合物的方法。本文还提供了通过抑制PDE10来治疗由此可治疗的疾病或疾病的方法，如肥胖症、非胰岛素依赖型糖尿病、精神分裂症、躁郁症、强迫症、亨廷顿病等。
Direct Amidation of Esters by Ball Milling**
作者：William I. Nicholson、Fabien Barreteau、Jamie A. Leitch、Riley Payne、Ian Priestley、Edouard Godineau、Claudio Battilocchio、Duncan L. Browne
DOI：10.1002/anie.202106412
日期：2021.9.27
The direct mechanochemical amidation of esters by ball milling is described. The operationally simple procedure requires an ester, an amine, and substoichiometric KOtBu and was used to prepare a large and diverse library of 78 amide structures with modest to excellent efficiency. Heteroaromatic and heterocyclic components are specifically shown to be amenable to this mechanochemical protocol. This
[EN] QUINAZOLINE DERIVATIVES, COMPOSITIONS, AND USES RELATED THERETO<br/>[FR] DÉRIVÉS DE QUINAZOLINE, COMPOSITIONS ET UTILISATIONS ASSOCIÉES
申请人：UNIV EMORY
公开号：WO2013181135A1
公开（公告）日：2013-12-05
The disclosure relates to quinazoline derivatives, compositions, and methods related thereto. In certain embodiments, the disclosure relates to inhibitors of NADPH-oxidases (Nox enzymes) and/or myeloperoxidase.
[EN] NMDA RECEPTOR MODULATORS AND USES THEREOF<br/>[FR] MODULATEURS DES RÉCEPTEURS NMDA ET UTILISATIONS DE CEUX-CI
申请人：CADENT THERAPEUTICS
公开号：WO2018119374A1
公开（公告）日：2018-06-28
Disclosed herein, in part, are heteroaromatic compounds and methods of use in treating neuropsychiatric disorders, e.g., schizophrenia and major depressive disorder. Pharmaceutical compositions and methods of making heteroaromatic compounds are provided. The compounds are contemplated to modulate the NMDA receptor.
