The metabolism of escitalopram is mainly hepatic, mediated primarily by CYP2C19 and CYP3A4 and, to a lesser extent, CYP2D6. Oxidative N-demethylation by the CYP enzyme system results in S-desmethylcitalopram (S-DCT) and S-didesmethylcitalopram (S-DDCT) - these metabolites do not contribute to the pharmacologic activity of escitalopram, and exist in the plasma in small quantities relative to the parent compound (28-31% and <5%, respectively). There is also some evidence that escitalopram is metabolized to a propionic acid metabolite by monoamine oxidase A and B in the brain, and that these enzymes constitute the major route of escitalopram metabolism in the brain.
The antidepressant escitalopram is predominantly metabolized by the polymorphic CYP2C19 enzyme. The authors investigated the effect of CYP2C19 genotype on exposure and therapeutic failure of escitalopram in a large patient population. A total of 4,228 escitalopram serum concentration measurements from 2,087 CYP2C19-genotyped patients 10-30 hours after drug intake were collected retrospectively from the drug monitoring database at Diakonhjemmet Hospital in Oslo. The patients were divided into subgroups based on CYP2C19 genotype: those carrying inactive (CYP2C19Null) and gain-of-function (CYP2C19*17) variant alleles. The between-subgroup differences in escitalopram exposure (endpoint: dose-harmonized serum concentration) and therapeutic failure (endpoint: switching to another antidepressant within 1 year after the last escitalopram measurement) were evaluated by multivariate mixed model and chi-square analysis, respectively. Compared with the CYP2C19*1/*1 group, escitalopram serum concentrations were significantly increased 3.3-fold in the CYP2C19Null/Null group, 1.6-fold in the CYP2C19*Null/*1 group, and 1.4-fold in the CYP2C19Null/*17 group, whereas escitalopram serum concentrations were significantly decreased by 10% in the CYP2C19*1/*17 group and 20% in the CYP1C19*17/*17 group. In comparison to the CYP2C19*1/*1 group, switches from escitalopram to another antidepressant within 1 year were 3.3, 1.6, and 3.0 times more frequent among the CYP2C19Null/Null, CYP2C19*1/*17, and CYP1C19*17/*17 groups, respectively. The CYP2C19 genotype had a substantial impact on exposure and therapeutic failure of escitalopram, as measured by switching of antidepressant therapy. The results support the potential clinical utility of CYP2C19 genotyping for individualization of escitalopram therapy.
Escitalopram is metabolized to S-demethylcitalopram (S-DCT) and S-didemethylcitalopram (S-DDCT). In humans, unchanged escitalopram is the predominant compound in plasma. At steady state, the concentration of the escitalopram metabolite S-DCT in plasma is approximately one-third that of escitalopram. The level of S-DDCT was not detectable in most subjects. In vitro studies show that escitalopram is at least 7 and 27 times more potent than S-DCT and S-DDCT, respectively, in the inhibition of serotonin reuptake, suggesting that the metabolites of escitalopram do not contribute significantly to the antidepressant actions of escitalopram. S-DCT and S-DDCT also have no or very low affinity for serotonergic (5-HT1-7) or other receptors including alpha- and beta-adrenergic, dopamine (D1-5), histamine (H1-3), muscarinic (M1-5), and benzodiazepine receptors. S-DCT and S-DDCT also do not bind to various ion channels including Na+, K+, Cl-, and Ca++ channels. In vitro studies using human liver microsomes indicated that CYP3A4 and CYP2C19 are the primary isozymes involved in the Ndemethylation of escitalopram.
Mainly hepatic. Escitalopram undergoes <i>N</i>-demethylation to <i>S</i>-demethylcitalopram (S-DCT) and <i>S</i>-didemethylcitalopram (S-DDCT). CYP3A4 and CYP2C19 are the enzymes responsible for this <i>N</i>-demethylation reaction.
Route of Elimination: Following oral administrations of escitalopram, the fraction of drug recovered in the urine as escitalopram and <i>S</i>-demethylcitalopram (S-DCT) is about 8% and 10%, respectively. The oral clearance of escitalopram is 600 mL/min, with approximately 7% of that due to renal clearance. Escitalopram is metabolized to S-DCT and <i>S</i>-didemethylcitalopram (S-DDCT).
Half Life: 27-32 hours
IDENTIFICATION AND USE: Escitalopram is a second-generation antidepressive agent. It is used for the acute and maintenance treatment of major depressive disorder in adults and in adolescents 12 to 17 years of age. HUMAN STUDIES: Antidepressant discontinuation syndrome (ADS) frequently occurs in patients who undergo an abrupt discontinuation of their antidepressant medication. For escitalopram ADS was observed in 14 of 25 patients. Frequent symptoms were dizziness (44%), muscle tension (44%), chills (44%), confusion or trouble concentrating (40%), amnesia (28%), and crying (28%). Major manifestations of escitalopram overdose were serotonin toxicity, QT prolongation, and bradycardia. Other symptoms accompanying escitalopram overdose, alone or in combination with other drugs and/or alcohol, included convulsions, coma, dizziness, hypotension, insomnia, nausea, vomiting, sinus tachycardia, and somnolence. Acute renal failure has been very rarely reported accompanying overdose. Escitalopram does not appear to be associated with an increased risk for major malformations but appears to increase the risk for low birth weight. In addition, the higher rates of spontaneous abortions have been observed. A case of serotonin toxicity due to in utero exposure to escitalopram was described. In human peripheral lymphocytes sister chromatid exchange increase caused by 5 and 10 ug/mL of escitalopram was found, while no increase was observed in DNA damage and micronucleus (MN) formation. Racemic form of the drug was not clastogenic in the in vitro chromosomal aberration assay in human lymphocytes. ANIMAL STUDIES: In a one-year toxicology study, 5 of 10 beagle dogs receiving oral racemic drug doses of 8 mg/kg/day died suddenly between weeks 17 and 31 following initiation of treatment. Sudden deaths were not observed in rats at doses of racemic drug up to 120 mg/kg/day. A subsequent intravenous dosing study demonstrated that in beagle dogs, racemic metabolites caused QT prolongation. Pathologic changes (degeneration/atrophy) were observed in the retinas of albino rats in the 2-year carcinogenicity study with racemic drug. There was an increase in both incidence and severity of retinal pathology in both male and female rats receiving 80 mg/kg/day. Similar findings were not present in rats receiving 24 mg/kg/day of racemic drug for two years, in mice receiving up to 240 mg/kg/day of racemic drug for 18 months, or in dogs receiving up to 20 mg/kg/day of racemic drug for one year. In two rat embryo/fetal development studies, oral administration of racemic drug (32, 56, or 112 mg/kg/day) to pregnant animals during the period of organogenesis resulted in decreased embryo/fetal growth and survival and an increased incidence of fetal abnormalities (including cardiovascular and skeletal defects) at the high dose. This dose was also associated with maternal toxicity in rats. In a rabbit study, no adverse effects on embryo/fetal development were observed at doses of racemic citalopram of up to 16 mg/kg/day. Racemic drug was mutagenic in the in vitro bacterial reverse mutation assay (Ames test) in 2 of 5 bacterial strains (Salmonella TA98 and TA1537) in the absence of metabolic activation. It was clastogenic in the in vitro Chinese hamster lung cell assay for chromosomal aberrations in the presence and absence of metabolic activation. Racemic drug was not mutagenic in the in vitro mammalian forward gene mutation assay (HPRT) in mouse lymphoma cells or in a coupled in vitro/in vivo unscheduled DNA synthesis (UDS) assay in rat liver. ECOTOXICITY STUDIES: There were noticeable gender differences in the behavior responses to escitalopram in zebrafish. At the end of exposures, both length and weight of the females exposed to 1.50 ug/L escitalopram were significantly less than the group of control fish. In addition, males exposed to 1.50 ug/L escitalopram were significantly shorter than control fish.
The antidepressant, antiobsessive-compulsive, and antibulimic actions of escitalopram are presumed to be linked to its inhibition of CNS neuronal uptake of serotonin. Escitalopram blocks the reuptake of serotonin at the serotonin reuptake pump of the neuronal membrane, enhancing the actions of serotonin on 5HT<sub>1A</sub> autoreceptors. SSRIs bind with significantly less affinity to histamine, acetylcholine, and norepinephrine receptors than tricyclic antidepressant drugs.
Absorption of escitalopram following oral administration is expected to be almost complete, with an estimated absolute bioavailability of approximately 80%. Tmax occurs after about 4-5 hours. Cmax and AUC appear to follow dose proportionality - at steady state, patients receiving 10mg of escitalopram daily had a Cmax of 21 ng/mL and a 24h AUC of approximately 360 ng*h/mL, while patients receiving 30mg daily had a roughly 3-fold increase in both Cmax and 24h AUC, comparatively.
After oral administration of escitalopram, approximately 8% of the total dose is eliminated in the urine as unchanged escitalopram and 10% is eliminated in the urine as S-desmethylcitalopram. The apparent hepatic clearance of escitalopram amounts to approximately 90% of the total dose.
来源:DrugBank
吸收、分配和排泄
分布容积
艾司西酞普兰似乎广泛分布于组织中，其表观分布体积大约为12-26升/千克。
Escitalopram appears to distribute extensively into tissues, with an apparent volume of distribution of approximately 12-26 L/kg.
来源:DrugBank
吸收、分配和排泄
清除
艾司西酞普兰的口服血浆清除率为600 mL/min，其中大约7%是由于肾脏清除。
The oral plasma clearance of escitalopram is 600 mL/min, of which approximately 7% is due to renal clearance.
/MILK/ Escitalopram is excreted in human breast milk. Limited data from women taking 10-20 mg escitalopram showed that exclusively breast-fed infants receive approximately 3.9% of the maternal weight-adjusted dose of escitalopram and 1.7% of the maternal weight-adjusted dose of desmethylcitalopram.
[EN] COMPOUNDS AND THEIR USE AS BACE INHIBITORS<br/>[FR] COMPOSÉS ET LEUR UTILISATION EN TANT QU'INHIBITEURS DE BACE
申请人：ASTRAZENECA AB
公开号：WO2016055858A1
公开（公告）日：2016-04-14
The present application relates to compounds of formula (I), (la), or (lb) and their pharmaceutical compositions/preparations. This application further relates to methods of treating or preventing Αβ-related pathologies such as Down's syndrome, β- amyloid angiopathy such as but not limited to cerebral amyloid angiopathy or hereditary cerebral hemorrhage, disorders associated with cognitive impairment such as but not limited to MCI ("mild cognitive impairment"), Alzheimer's disease, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegeneration associated with diseases such as Alzheimer's disease or dementia, including dementia of mixed vascular and degenerative origin, pre-senile dementia, senile dementia and dementia associated with Parkinson's disease.
[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] SPIROLACTAM CGRP RECEPTOR ANTAGONISTS<br/>[FR] ANTAGONISTES DE RÉCEPTEUR DE CGRP À BASE DE SPIROLACTAME
申请人：MERCK SHARP & DOHME
公开号：WO2013169567A1
公开（公告）日：2013-11-14
The present invention is directed to spirolactam analogues which are antagonists of CGRP receptors and useful in the treatment or prevention of diseases in which CGRP is involved, such as migraine. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which CGRP is involved.
[EN] PROCESSES USEFUL FOR THE SYNTHESIS OF (R)-1-{2-[4'-(3-METHOXYPROPANE-1-SULFONYL)-BIPHENYL-4-YL]-ETHYL}-2-METHYL-PYRROLIDINE<br/>[FR] PROCÉDÉS UTILES POUR LA SYNTHÈSE DE LA (R)-1-{2-[4'-(3-MÉTHOXYPROPANE-1-SULFONYL)-BIPHÉNYL-4-YL]-ÉTHYL}-2-MÉTHYL-PYRROLIDINE
申请人：ARENA PHARM INC
公开号：WO2009128907A1
公开（公告）日：2009-10-22
Processes useful for making a pharmaceutically useful compound according to Formula (I), forms of such a compound, and intermediates useful in such processes are described.
根据公式（I）制备药用化合物的有用过程，以及该化合物的形式和在这些过程中有用的中间体被描述。
[EN] IMIDAZOPYRIDINE COMPOUNDS AND USES THEREOF<br/>[FR] COMPOSÉS IMIDAZOPYRIDINE ET LEURS UTILISATIONS
申请人：NEOMED INST
公开号：WO2014117274A1
公开（公告）日：2014-08-07
This invention generally relates to substituted imidazopyridine compounds, particularly substituted 4-(imidazo[1,2-a]pyridin-2-yl)benzamide compounds and salts thereof. This invention also relates to pharmaceutical compositions and kits comprising such a compound, uses of such a compound (including, for example, treatment methods and medicament preparations), processes for making such a compound, and intermediates used in such processes.
