Sertraline is heavily metabolized in the liver and has one major active metabolite. It undergoes N-demethylation to form N-desmethylsertraline, which is much less potent in its pharmacological activity than sertraline. In addition to N-demethylation, sertraline metabolism involves N-hydroxylation, oxidative deamination, and finally, glucuronidation. The metabolism of sertraline is mainly catalyzed by CYP3A4 and CYP2B6, with some activity accounted for by CYP2C19 and CYP2D6.
Sertraline undergoes extensive metabolism. The parent drug is N-demethylated, followed by glucuronidation, deamination, or both. Most metabolites in the urine are alpha-hydroxy-ketone glucuronides.
Depression is one of the most common psychiatric disorders. A variety of different chemical structures have been found to have antidepressant activity. The number is constantly growing; however, as yet, no one group has been found to have a clear therapeutic advantage over the others. The major indication for antidepressant drugs is depression, but a number of side effects have been established by clinical experience and controlled trials. It is clear that, to some extent, any drug or chemical substance administered to the mother is able to cross the placenta unless it is destroyed or altered during metabolism. Placental transport of maternal substrates to the fetus and of substances from the fetus to the mother is established at about the fifth week of fetal life. Traditionally, teratogenic effects of antidepressants or other drugs have been noted as anatomic malformation. It is clear that these are dose- and time-related and that the fetus is at great risk during the first 3 months of gestation. However, it is possible for antidepressants to exert their effects on the fetus at other times during pregnancy as well as to infants during lactation. Administration of antidepressants to pregnant women presents a unique problem for the physician. Not only must maternal pharmacologic mechanisms be taken into consideration when prescribing an antidepressant drug, but the fetus must also be regarded as a potential recipient of the drug. Certain results are evident with regard to drugs administered during lactation. It is essential that physicians need to be aware of the results of animal studies in this area and of the potential risk of maternal drug ingestion to the suckling infant.
来源:Hazardous Substances Data Bank (HSDB)
代谢
舍曲林已知的人类代谢物包括N-去甲舍曲林。
Sertraline has known human metabolites that include N-desmethylsertraline.
Extensively metabolized in the liver. Sertraline metabolism involves <i>N</i>-demethylation, <i>N</i>-hydroxylation, oxidative deamination, and glucuronidation of sertraline carbamic acid. Sertraline undergoes <i>N</i>-demethylation primarily catalyzed by cytochrome P450 (CYP) 2B6, with CYP2C19, CYP3A4 and CYP2D6 contributing to a lesser extent. Deamination occurs via CYP3A4 and CYP2C19. <i>In vitro</i> studies have shown that monoamine oxidase A and B may also catalyze sertraline deamination. Sertraline <i>N</i>-carbamoyl glucuronidation has also been observed in human liver microsomes.
Route of Elimination: Sertraline is extensively metabolized and excretion of unchanged drug in urine is a minor route of elimination.
Half Life: The elimination half-life of sertraline is approximately 25-26 hours. The elimination half-life of desmethylsertraline is approximately 62-104 hours.
IDENTIFICATION: Sertraline is a selective serotonin reuptake inhibitor antidepressant agent. Sertraline hydrochloride is a white solid crystal or powder. It is soluble in water and slightly soluble in isopropyl alcohol. Indications: Psychoanaleptic Antidepressant and bicyclic antidepressant Accepted: Major mental depression and prevention of relapse and recurrence of depression. HUMAN EXPOSURE: Main risks and target organs: Sertraline is a selective serotonin reuptake inhibitor (SSRI). When taken alone it is safer in overdose than most other classes of antidepressants. Patients who ingest a sertraline overdose generally experience only mild neurological and gastroenterological symptoms; significant cardiovascular toxicity is unusual. The serotonergic effects of sertraline may be enhanced when sertraline is combined with tricyclic antidepressants, monoamine oxidase inhibitors (MAOIs), carbamazepine, lithium or serotonergic substances. A life threatening serotonin syndrome consisting of hyperthermia, tremor and convulsions can develop when sertraline is ingested with these drugs. Summary of clinical effects: Lightheadedness, drowsiness, tremor in upper extremities; nausea, vomiting, diarrhea. Diagnosis: Diagnosis of sertraline poisoning is clinical and based on history of overdose and/or access to sertraline and the presence of minor neurological and/or gastroenterological symptoms. Co-ingestion of tricyclic antidepressants and/or MAOIs should be suspected and the diagnosis of the serotonin syndrome should be considered in the presence of three or more of the following symptoms: behavioral change (confusion or hypomania), agitation, myoclonus, ocular clonus, sustained ankle clonus, hyperreflexia, sweating, shivering, tremor, diarrhea, motor incoordination, muscle rigidity, fever. The differential diagnoses include neuroleptic malignant syndrome, acute poisoning with strychnine, acute sepsis, or severe metabolic disturbance. Contraindications: Absolute: Hypersensitivity to sertraline. Children less than 15 years old. Co-administration of sumatriptan, non selective monoamine oxidase inhibitor (MAOI) and MAOI B-selective antidepressants. Relative: Co-administration of MAOI A-selective antidepressants. Pregnancy and breast feeding. Routes of exposure: Oral: Sertraline is available as capsules, thus ingestion is the most common route of exposure. Kinetics: Absorption by route of exposure: Sertraline is slowly and completely absorbed from the gastrointestinal tract. Peak plasma concentrations (Cmax) occur between 4.5 and 8.5 hours after ingestion of a single dose. The presence of food slightly increases sertraline bioavailability and Cmax increases by 25%. Sertraline undergoes extensive first pass metabolism in the liver. Distribution by route of exposure: Widely distributed throughout body tissues and highly bound to plasma proteins (about 98 %). The apparent volume of distribution is 20 L/kg. The plasma sertraline level was reported to be 20 to 48 ug/L after at least 1 week of treatment with 100 mg sertraline daily, and it ranged from 40 to 187 ug/L after 200 mg. Plasma sertraline concentrations increase proportionally to the administered dose, unlike fluoxetine and paroxetine. Cmax and area under the plasma concentration-time curve values are increased, and elimination half-life is prolonged in elderly patients but these changes do not appear to warrant dose adjustment in this patient group. Biological half-life by route of exposure: After oral doses, plasma half-life is 24 to 26 hours. Metabolism: Sertraline is extensively metabolized in the liver to N-desmethylsertraline, whose half-life is 2 to 3 times longer than sertraline. N-desmethylsertraline is 10 times less active as an inhibitor of serotonin re-uptake in vitro, and has almost no activity in animal models. Elimination and excretion: N-desmethylsertraline is oxidatively deaminated to desmethylsertraline ketone which, in turn, undergoes hydroxylation to an alpha-hydroxyketone and alcohol; these metabolites are then conjugated and excreted in equal amounts in the urine and feces; a small amount of unchanged drug (less than 0.2 %) is excreted in the urine. There are few data about the excretion of sertraline and its metabolites in breast milk did not detect sertraline in the serum of an infant exclusively breastfed by his mother, after 3 weeks and 7 weeks of treatment, although sertraline could be detected in breast milk. Pharmacology and toxicology: Mode of action: Toxicodynamics: Sertraline is a potent inhibitor of serotonin re-uptake by central nervous system neurones and may interact with other drugs or circumstances which cause serotonin release. The enhancement of the serotonergic effects may produce a life-threatening serotonin syndrome. Sertraline, like the other SSRIs fluoxetine and paroxetine, can inhibit in vivo and in vitro, the hepatic isoenzyme 2D6 of the cytochrome P450 system (CYP2D6), which is involved in the oxidative metabolism of numerous drugs. Caution should be used when combining sertraline with CYP2D6 substrates (desipramine, nortriptyline, haloperidol, thioridazine, flecainide, codeine, propranolol, metoprolol), as sertraline can cause a significant increase in the serum concentrations of these drugs. In vitro studies suggest that sertraline may be a substrate for, but does not inhibit another hepatic iso-enzyme of the cytochrome P450 system, CYP3A3/4, which is involved in the metabolism of carbamazepine. A study performed in healthy volunteers showed no evidence of a pharmacodynamic drug-drug interaction between sertraline and carbamazepine. Pharmacodynamics: Sertraline specifically inhibits central nervous system neuronal re-uptake of serotonin, thus increasing the concentration of the serotonin at the synapse and enhancing of serotonergic neuronal transmission. The increased availability of serotonin is thought to be linked with the improvement in depression accounted for by sertraline treatment. Sertraline has no direct effect on the re-uptake of noradrenaline, dopamine or GABA. Unlike most tricyclic antidepressants, it has no significant affinity for alpha1-adrenergic, H1-histamine, and muscarinic receptors. Furthermore, sertraline does not show significant affinity for D1 and D2 dopaminergic, alpha2 and � adrenergic, benzodiazepine and opioid receptors. The selectivity of sertraline may account for the lower incidence of some adverse effects such as sedation, orthostatic hypotension and anticholinergic effects. Like tricyclic antidepressants, MAOIs, and other SSRIs, sertraline significantly reduces REM (rapid eye movement) sleep density, REM time and the REM percentage of total sleep time in patients with major depression. Adults: Overdoses up to 4500 mg of sertraline alone produced mild drowsiness and serious toxicity did not develop in the 48 patients. Children: In a case series of pediatric overdoses, sertraline caused no symptoms in 10 children less than 5 year old; eight of these received gastrointestinal decontamination. Interactions: Coadministration of drugs increasing the level of serotonin: tricyclic antidepressants, other SSRIs, MAOIs, reversible inhibitors of monoamine oxidase (RIMAs), lithium, may cause a serotonin syndrome. At least 2 weeks should elapse after discontinuing a MAOI before starting therapy with sertraline. Sertraline should be stopped at least 1 week before beginning MAOI therapy. Sertraline should not be concomitantly used 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 1 week after cessation of sertraline. A clinical study involving 103 episodes of migraine in patients taking any SSRIs, did not show evidence of significant adverse effects. Cimetidine inhibits the metabolism of sertraline, leading to increased plasma concentrations; close clinical monitoring and/or reduced sertraline doses are recommended. By extrapolation from data available for fluoxetine, drug interactions with oral anticoagulants and carbamazepine might occur, though in vitro and in vivo studies performed with carbamazepine did not show evidence of interactions and though no cases have been reported to date. Treatment with sertraline was associated with worsening and/or recurrence of the lysergide (LSD) flashbacks in two adolescents with a long history of polydrug abuse. They had stopped taking LSD 10 months before sertraline therapy. Main adverse effects: The most common adverse effects reported with therapeutic doses of sertraline are primarily nausea, diarrhea, dyspepsia, dry mouth, insomnia, somnolence, tremor, dizziness, headache and male sexual dysfunction (delayed ejaculation). These adverse effects are reported to occur in 10 to 20 % of patients, and they cause patients to stop therapy in approximately 1 to 4 % of cases. Manic episodes may be provoked in patients with bipolar disorders. If this occurs, sertraline should be discontinued and a sedative antipsychotic drug should be administered. Less common adverse effects include, pruritus, alopecia, and extrapyramidal symptoms. Several cases of hyponatremia and the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) have been reported, mainly in elderly patients. Galactorrhea developed in a 40 year old woman receiving sertraline 150 mg/day during 11 week of dosing. Several cases of stuttering have been described. Bruxism causing significant physical consequences was associated with sertraline and other SSRIs in a case series reported. A case of anisocoria was reported. Increase in serum AST and ALT levels has occurred, and returned to normal after treatment was stopped. Sertraline caused prolonged bleeding time in one patient; agranulocytosis was also reported. ANIMAL/PLANT STUDIES: Symptomatology: decreased food intake, hyperactivity, muscular weakness, convulsions. Chronic toxicity: oral doses of serataline for 6 and 12 months; several adverse effects occurred during the first weeks, including hypersalivation, abnormal movements of the head, disorientation, agitation; resulted in convulsions in 2 dogs; all of these effects where temporary and resolved spontaneously despite continuation of sertraline administration. An increase of liver weight associated with a rise in plasma alkaline phosphatase enzymes was noted, due to the properties of enzyme induction of sertraline. Carcinogenicity: Animal studies: In rats a slight increase in the number of follicular and thyroid adenomas was observed in relation with hepatic enzyme induction; these findings cannot be extrapolated to man, because of species differences in the metabolic mechanisms. Teratogenicity: Animal studies: Fertility in rats was not affected. Sertraline did not show embryotoxic or teratogenic properties in rat and rabbit models. However, in the rat, sertraline caused a delay in fetal ossification and a delay in apparition of teeth in the young. A decrease in food intake inducing a delay in growth in the young, proportional to the administered dose, sometimes associated with hyperactivity, was also observed. Mutagenicity: In vitro and in vivo: sertraline did not show mutagenicity for chromosomes and genes.
The exact mechanism of action sertraline is not fully known, but the drug appears to selectively inhibit the reuptake of serotonin at the presynaptic membrane. This results in an increased synaptic concentration of serotonin in the CNS, which leads to numerous functional changes associated with enhanced serotonergic neurotransmission. It is suggested that these modifications are responsible for the antidepressant action observed during long term administration of antidepressants. It has also been hypothesized that obsessive-compulsive disorder is caused by the dysregulation of serotonin, as it is treated by sertraline, and the drug corrects this imbalance.
Liver test abnormalities have been reported to occur in up to 1% of patients on sertraline, but elevations are usually modest and infrequently require dose modification or discontinuation. Rare instances of acute, clinically apparent episodes of liver injury with marked liver enzyme elevations with or without jaundice have been reported in patients on sertraline. The onset of injury is usually within 2 to 24 weeks and the pattern of serum enzyme elevations has varied from hepatocellular to mixed and cholestatic. Autoimmune (autoantibodies) and immunoallergic features (rash, fever, eosinophilia) are uncommon. Acute liver failure due to sertraline has been described but is very rare.
Following once-daily administration of 50 to 200 mg for two weeks, the mean peak plasma concentrations (Cmax) of sertraline occurred between 4.5 to 8.4 hours after administration, and measured at 20 to 55 μg/L. Steady-state concentrations are reached after 1 week following once-daily administration, and vary greatly depending on the patient. Bioavailability has been estimated to be above 44%. The area under the curve in healthy volunteers after a 100mg dose of sertraline was 456 μg × h/mL in one study. **Effects of food on absorption** The effects of food on the bioavailability of the sertraline tablet and oral concentrate were studied in subjects given a single dose with and without food. For the tablet, AUC was slightly increased when sertraline was administered with food, the Cmax was 25% greater, and the time to peak plasma concentration was shortened by about 2.5 hours. For the oral concentrate preparation of sertraline, peak concentration was prolonged by approximately 1 hour with the ingestion of food.
Since sertraline is extensively metabolized, excretion of unchanged drug in the urine is a minor route of elimination, with 12-14% of unchanged sertraline excreted in the feces.
Sertraline is widely distributed, and its volume of distribution is estimated to be more than 20L/kg. Post-mortem studies in humans have measured liver tissue concentrations of 3.9–20 mg/kg for sertraline and between 1.4 to 11 mg/kg for its active metabolite, N-desmethyl-sertraline (DMS). Studies have also determined sertraline distributes into the brain, plasma, and serum.
In pharmacokinetic studies, the clearance of a 200mg dose of sertraline in studies of both young and elderly patients ranged between 1.09 ± 0.38 L/h/kg - 1.35 ± 0.67 L/h/kg.
An Expedient Total Synthesis of cis-(+)-Sertraline from d-Phenylglycine
摘要：
An efficient and practical total synthesis of cis-(+)-Sertraline is developed involving intramolecular Friedel-Crafts cyclization of an appropriately tailored D-phenylglycine. (C) 2000 Elsevier Science Ltd. All rights reserved.
[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] SUBSTITUTED N-HETEROCYCLIC CARBOXAMIDES AS ACID CERAMIDASE INHIBITORS AND THEIR USE AS MEDICAMENTS<br/>[FR] CARBOXAMIDES N-HÉTÉROCYCLIQUES SUBSTITUÉS UTILISÉS EN TANT QU'INHIBITEURS DE LA CÉRAMIDASE ACIDE ET LEUR UTILISATION EN TANT QUE MÉDICAMENTS
申请人：BIAL BIOTECH INVEST INC
公开号：WO2021055627A1
公开（公告）日：2021-03-25
The invention provides substituted N-heterocyclic carboxamides and related compounds, compositions containing such compounds, medical kits, and methods for using such compounds and compositions to treat a medical disorder, e.g., cancer, lysosomal storage disorder, neurodegenerative disorder, inflammatory disorder, in a patient.
[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.
New Drug Delivery System for Crossing the Blood Brain Barrier
申请人：Lipshutz H. Bruce
公开号：US20070203080A1
公开（公告）日：2007-08-30
New ubiquinol analogs are disclosed, as well as methods of using these compounds to deliver drug moieties to the body.
新的泛醌类似物被披露，以及利用这些化合物将药物基团输送到人体的方法。
[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.
