Vortioxetine is extensively metabolized primarily through oxidation via cytochrome P450 isozymes CYP2D6, CYP3A4/5, CYP2C19, CYP2C9, CYP2A6, CYP2C8 and CYP2B6 and subsequent glucuronic acid conjugation. CYP2D6 is the primary enzyme catalyzing the metabolism of vortioxetine to its major, pharmacologically inactive, carboxylic acid metabolite, and poor metabolizers of CYP2D6 have approximately twice the vortioxetine plasma concentration of extensive metabolizers.
Vortioxetine is extensively metabolized primarily through oxidation via cytochrome P450 isozymes CYP2D6, CYP3A4/5, CYP2C19, CYP2C9, CYP2A6, CYP2C8 and CYP2B6 and subsequent glucuronic acid conjugation. CYP2D6 is the primary enzyme catalyzing the metabolism of vortioxetine to its major, pharmacologically inactive, carboxylic acid metabolite, and poor metabolizers of CYP2D6 have approximately twice the vortioxetine plasma concentration of extensive metabolizers.
All metabolites detected in human hepatocytes were also present in dogs, mice and rats (plasma and/or urine) in vivo, except for a glucuronide conjugate of monohydroxy-Vortioxetine which was not found in mice or rats. Among all species tested, rabbit hepatocytes appeared to have the metabolite profile closer to human hepatocyte metabolite profile.
IDENTIFICATION AND USE: Vortioxetine is a white to very slightly beige powder formulated into film-coated tablets. It is used for the management of major depressive disorders in adults. HUMAN EXPOSURE AND TOXICITY: There is limited clinical trial experience regarding human overdosage with vortioxetine. In pre-marketing clinical studies, cases of overdose were limited to patients who accidentally or intentionally consumed up to a maximum dose of 40 mg of vortioxetine. The maximum single dose tested was 75 mg in men. Ingestion of vortioxetine in the dose range of 40 to 75 mg was associated with increased rates of nausea, dizziness, diarrhea, abdominal discomfort, generalized pruritus, somnolence, and flushing. Toxicity may also occur at therapeutic dosage levels of vortioxetine. Potentially life-threatening serotonin syndrome has been reported with serotonergic antidepressants, including vortioxetine, when used alone, but particularly with concurrent use of other serotonergic drugs (including serotonin (5-hydroxytryptamine; 5-HT) type 1 receptor agonists ("triptans"), tricyclic antidepressants, buspirone, fentanyl, lithium, tramadol, tryptophan, and St. John's wort (Hypericum perforatum)) and with drugs that impair the metabolism of serotonin (particularly monoamine oxidase (MAO) inhibitors, both those used to treat psychiatric disorders and others, such as linezolid and methylene blue). Manifestations of serotonin syndrome may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, and hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, and incoordination), seizures, and/or GI symptoms (e.g., nausea, vomiting, and diarrhea). Concurrent or recent (i.e., within 2 weeks) therapy with MAO inhibitors intended to treat psychiatric disorders is contraindicated. Use of an MAO inhibitor intended to treat psychiatric disorders within 3 weeks of vortioxetine discontinuance also is contraindicated. Vortioxetine also should not be initiated in patients who are being treated with other MAO inhibitors such as linezolid or IV methylene blue. If concurrent therapy with vortioxetine and other serotonergic drugs is clinically warranted, the patient should be made aware of the potential increased risk for serotonin syndrome, particularly during initiation of therapy or when dosage is increased. Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term studies. These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients over age 24; there was a trend toward reduced risk with antidepressant use in patients aged 65 and older. Vortioxetine was not genotoxic in an in vitro chromosome aberration assay in cultured human lymphocytes. ANIMAL STUDIES: The acute oral single dose toxicity of vortioxetine is relatively low with a maximum tolerated dose (MTD) in mice and rats of 300 and 500 mg/kg, respectively. Clinical signs consisted of marked sensitivity to touch and disturbance, rapid breathing, and brown perinasal staining in rats administered 500 mg/kg. In mice, tremors, sensitivity to touch, eyes partly closed, and hypoactivity were seen after 200 and 300 mg/kg, as well as rapid, noisy and/or labored breathing, incoordination, unsteady gait, leaning, salivation, and hyperactivity after 400 and 500 mg/kg. When administered as two vortioxetine doses given an hour apart (200 mg/kg), clinical signs included convulsions, and resulted in death. Carcinogenicity studies were conducted in which mice and rats were given oral doses of vortioxetine up to 50 and 100 mg/kg/day for male and female mice, respectively, and 40 and 80 mg/kg/day for male and female rats, respectively, for 2 years. In rats, the incidence of benign polypoid adenomas of the rectum was statistically significantly increased in females. These were considered related to inflammation and hyperplasia and possibly caused by an interaction with a vehicle component of the formulation used for the study. The finding did not occur in male rats. In mice, vortioxetine was not carcinogenic in males or females. Vortioxetine caused developmental delays when administered during pregnancy to rats and rabbits. Developmental delays were also seen after birth in rats treated with vortioxetine during pregnancy and through lactation. There were no teratogenic effects in rats or rabbits treated with the drug during organogenesis. Treatment of rats with vortioxetine at doses up to 120 mg/kg/day had no effect on male or female fertility. Vortioxetine was not genotoxic in the in vitro bacterial reverse mutation assay (Ames test) and in the in vivo rat bone marrow micronucleus assay.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
肝毒性
一小部分患者出现肝功能测试异常（
Liver test abnormalities occur in a small proportion of patients (
◉ Summary of Use during Lactation:Amounts of vortioxetine in milk appear to be low. If vortioxetine is required by the mother, it is not a reason to discontinue breastfeeding. However, until more data are available, vortioxetine should be used with careful infant monitoring during breastfeeding.
◉ Effects in Breastfed Infants:Three lactating mothers were taking vortioxetine for depression, two were taking 10 mg once daily and one was taking 20 mg once daily. All mothers were exclusively breastfeeding their infants aged 1, 2 and 6 months of age. No mothers reported any unusual behavior in their infants.
A woman who was taking a vortioxetine dose of 76.1 mcg/kg daily partially breastfed her infant. She did not observe any adverse effects in her infant.
◉ Effects on Lactation and Breastmilk:Vortioxetine has caused hyperprolactinemia and galactorrhea in some patients.
An observational study looked at outcomes of 2859 women who took an antidepressant during the 2 years prior to pregnancy. Compared to women who did not take an antidepressant during pregnancy, mothers who took an antidepressant during all 3 trimesters of pregnancy were 37% less likely to be breastfeeding upon hospital discharge. Mothers who took an antidepressant only during the third trimester were 75% less likely to be breastfeeding at discharge. Those who took an antidepressant only during the first and second trimesters did not have a reduced likelihood of breastfeeding at discharge. The antidepressants used by the mothers were not specified.
A retrospective cohort study of hospital electronic medical records from 2001 to 2008 compared women who had been dispensed an antidepressant during late gestation (n = 575) to those who had a psychiatric illness but did not receive an antidepressant (n = 1552) and mothers who did not have a psychiatric diagnosis (n = 30,535). Women who received an antidepressant were 37% less likely to be breastfeeding at discharge than women without a psychiatric diagnosis, but no less likely to be breastfeeding than untreated mothers with a psychiatric diagnosis. None of the mothers were taking vortioxetine.
In a study of 80,882 Norwegian mother-infant pairs from 1999 to 2008, new postpartum antidepressant use was reported by 392 women and 201 reported that they continued antidepressants from pregnancy. Compared with the unexposed comparison group, late pregnancy antidepressant use was associated with a 7% reduced likelihood of breastfeeding initiation, but with no effect on breastfeeding duration or exclusivity. Compared with the unexposed comparison group, new or restarted antidepressant use was associated with a 63% reduced likelihood of predominant, and a 51% reduced likelihood of any breastfeeding at 6 months, as well as a 2.6-fold increased risk of abrupt breastfeeding discontinuation. Specific antidepressants were not mentioned.
Potentially serious, sometimes fatal adverse reactions may occur in patients who are receiving or have recently received a monoamine oxidase (MAO) inhibitor and then initiate therapy with serotonergic antidepressants or in those who received SSRI or SNRI therapy shortly before initiation of an MAO inhibitor. Concomitant use of MAO inhibitors intended to treat psychiatric disorders with vortioxetine is contraindicated. In addition, at least 2 weeks should elapse between discontinuance of an MAO inhibitor intended to treat psychiatric disorders and initiation of vortioxetine and at least 3 weeks should elapse between discontinuance of vortioxetine and initiation of an MAO inhibitor intended to treat psychiatric disorders.
Concomitant use of vortioxetine and a selective serotonin-reuptake inhibitor (SSRI) or selective serotonin- and norepinephrine-reuptake inhibitor (SNRI) is associated with a risk of serious, sometimes fatal, serotonin syndrome. If concomitant use of vortioxetine and an SSRI or SNRI is clinically warranted, patients should be advised of the increased risk for serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome manifestations occur, treatment with vortioxetine and the concurrently administered SSRI or SNRI should be discontinued immediately and supportive and symptomatic treatment should be initiated.
The maximal plasma vortioxetine concentration (Cmax) after dosing is reached within 7 to 11 hours postdose. Absolute bioavailability is 75%. No effect of food on the pharmacokinetics was observed.
Following a single oral dose of [14C]labeled vortioxetine, approximately 59% and 26% of the administered radioactivity was recovered in the urine and feces, respectively as metabolites. Negligible amounts of unchanged vortioxetine were excreted in the urine up to 48 hours.
Vortioxetine is a new multi-modal drug against major depressive disorder with high affinity for a range of different serotonergic targets in the CNS. We report the (11)C-labeling of vortioxetine with (11)C-MeI using a Suzuki-protocol that allows for the presence of an unprotected amine. Preliminary evaluation of (11)C-vortioxetine in a Danish Landrace pig showed rapid brain uptake and brain distribution in accordance with the pharmacological profile, all though an unexpected high binding in cerebellum was also observed. (11)C-vortioxetine displayed slow tracer kinetics with peak uptake after 60 min and with limited wash-out from the brain. Further studies are needed but this radioligand may prove to be a valuable tool in unraveling the clinical effects of vortioxetine.
Regioselective C–H Thioarylation of Electron-Rich Arenes by Iron(III) Triflimide Catalysis
作者：Amy C. Dodds、Andrew Sutherland
DOI：10.1021/acs.joc.1c00448
日期：2021.4.16
iron(III) triflimide allowed the efficient thiolation of a range of arenes, including anisoles, phenols, acetanilides, and N-heterocycles. The method was applicable for the late-stage thiolation of tyrosine and tryptophan derivatives and was used as the keystep for the synthesis of pharmaceutically relevant biaryl sulfur-containing compounds such as the antibiotic dapsone and the antidepressant vortioxetine
[EN] PERMANENTLY POSITIVELY CHARGED ANTIDEPRESSANTS<br/>[FR] ANTIDÉPRESSEURS CHARGÉS POSITIVEMENT EN PERMANENCE
申请人：UNIV AARHUS
公开号：WO2013026455A1
公开（公告）日：2013-02-28
The present invention provides compounds comprising a substructure of below formula 3: or a salt or prodrug thereof and the use of such compounds in treatment of e.g. CNS disorders.
[EN] AN IMPROVED PROCESS FOR THE PREPARATION OF VORTIOXETINE AND SALTS THEREOF<br/>[FR] PROCÉDÉ AMÉLIORÉ POUR LA PRÉPARATION DE VORTIOXÉTINE ET DE SES SELS
申请人：PIRAMAL ENTPR LTD
公开号：WO2019155352A1
公开（公告）日：2019-08-15
The present invention relates to a novel crystalline polymorphic form of 1-[2-(2,4-dimethyl- phenylsulfanyl)-phenyl]-piperazine hydrochloride; commonly known as vortioxetine hydrochloride (hereafter referred to as the compound (Ia) and process for its preparation comprising of treating the compound (Ia) (as described herein) with a ketone solvent or mixture of ketone solvent with other solvents. The present invention also relates to an improved process for the preparation of vortioxetine hydrobromide (Ia), comprising reacting the compound (I) (as described herein) with hydrogen bromide solution in acetic acid.
[EN] NEW PROCESS FOR THE SYNTHESIS OF 1-(2-((2,4-DIMETHYLPHENYL)THIO)PHENYL)PIPERAZINE<br/>[FR] NOUVEAU PROCÉDÉ POUR LA SYNTHÈSE DE 1-(2-((2,4-DIMÉTHYLPHÉNYL)THIO)PHÉNYL)PIPÉRAZINE
申请人：LEK PHARMACEUTICALS
公开号：WO2014161976A1
公开（公告）日：2014-10-09
The present invention provides new intermediate compounds or formulae (III) and (IVa), and salts thereof, and their use in a new synthetic process for the production of 1-(2-((2,4- dimethylphenyl)thio)phenyl)piperazine (vortioxetine) an experimental drug under development for the treatment of depression and anxiety.
