The purpose of this study was to compare the disposition and the metabolic pattern of Reboxetine in several species, including man. (14)C-Reboxetine was given orally to the rat, the dog, the monkey (5 mg/kg) and man (2 and 4 mg/kg). Radioactivity was eliminated both by the renal and faecal route in the rat and the dog, mainly in urine in the monkey and man. Reboxetine was extensively metabolized. A number of urinary metabolites were quantified by radio-HPLC and tentatively identified by comparison with the retention times of reference compounds. Suggested routes of metabolic transformation are: 2-O-dealkylation; hydroxylation of the ethoxyphenoxy ring; oxidation of the morpholine ring; morpholine ring-opening; and combinations of these. Metabolites were partially or completely conjugated with glucuronic acid and/or sulphuric acid.
Reboxetine is predominantly metabolized in vitro via cytochrome P4503A (CYP3A4). In vitro studies have shown that reboxetine does not inhibit the activity of the following isozymes of cytochrome P450: CYP1A2, CYP2C9, CYP2C19, and CYP2E1. Reboxetine inhibits both CYP2D6 and CYP3A4 with low binding affinities, but has shown no effect on the in vivo clearance of drugs metabolized by these enzymes. Reboxetine should be co-prescribed with caution with potent inhibitors of CYP3A4.
Reboxetine is metabolized by dealkylation, hydroxylation and oxidation followed
by glucuronide or sulphate conjugation. It is metabolized by the cytochrome P450
CYP isoenzyme 3A4.
Half Life: 12.5 hours
Reboxetine is a selective inhibitor of noradrenaline reuptake. It inhibits noradrenaline reuptake <i>in vitro</i> to a similar extent to the tricyclic antidepressant desmethylimipramine. Reboxetine does not affect dopamine or serotonin reuptake and it has low <i>in vivo</i> and <i>in vitro</i> affinity for adrenergic, cholinergic, histaminergic, dopaminergic and serotonergic receptors.
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).
In vitro metabolism studies indicate that reboxetine is primarily metabolised by the CYP3A4 isozyme of cytochrome P450; reboxetine is not metabolized by CYP2D6. Therefore potent inhibitors of CYP3A4 (ketoconazole, nefazodone, erythromycin and fluvoxamine), would be expected to increase plasma concentrations of reboxetine. In a study in healthy volunteers, ketoconazole, a potent inhibitor of CYP3A4, was found to increase plasma concentrations of the reboxetine enantiomers by approximately 50%. Because of reboxetine's narrow therapeutic margin, inhibition of elimination is a major concern. Reboxetine, therefore should not be given together with drugs known to inhibit CYP3A4 such as azole antifungal agents, macrolide antibiotics such as erythromycin, or fluvoxamine.
Multiple samples of blood and milk were obtained over a dose interval at steady-state from four women who were taking reboxetine for postnatal depression. Drug concentrations in plasma and milk were measured by high performance liquid chromatography and milk/plasma ratio (M/P), absolute infant dose and relative infant dose were estimated by standard methods. Their four, breastfed, infants were also examined clinically, and a blood sample was taken for drug analysis. The median (range) dose taken by the women was 6 (4-10) mg/day. There was no significant difference in reboxetine concentration between paired fore-and hind-milk samples. The mean (95% CI) M/P was 0.06 (0.03, 0.09). Absolute infant dose was 1.7 (0.7, 2.4) ug/kg/day for reboxetine while the relative infant dose was 2.0% (1.3, 2.7%). ... The concentrations of reboxetine in plasma from the four infants were <4 ug/L, 2.6 ug/L, 2.3 ug/L and 5 ug/L, respectively.
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
瑞波昔汀已知会排泄在母乳中。
Reboxetine is known to be excreted in breast milk.
The drug appears to be distributed into total body water. Reboxetine is 97% bound to human plasma proteins in young and 92% in elderly (with affinity markedly higher for alpha1 acid glycoprotein than albumin), with no significant dependence of the concentration of drug.
After oral administration of a single 4 mg reboxetine dose to healthy volunteers, peak levels of about 130 ng/mL are achieved within 2 hr post-dosing. Data indicate that absolute bioavailability is at least 60%. Reboxetine plasma levels decreased monoexponentially with a half-life of about 13 hr. Steady-state conditions are observed within 5 days. Linearity of the pharmacokinetics was shown in the range of single oral doses in the clinically recommended dose-ranges.
Commercial Synthesis of (S,S)-Reboxetine Succinate: A Journey To Find the Cheapest Commercial Chemistry for Manufacture
摘要：
The development of a synthetic process for (S,S)-reboxetine succinate, a candidate for the treatment of fibromylagia, is disclosed from initial scale-up to deliver material for registrational stability testing through to commercial route evaluation and subsequent nomination. This entailed evaluation of several alternative routes to result in what would have been a commercially attractive process for launch of the compound.
[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.
The present invention provides certain imidazole carboxamide derivatives, pharmaceutical compositions thereof, methods of using the same and processes for preparing the same.
[EN] DIAZABICYCLO[4.3.1]DECANE DERIVATIVES FOR TREATMENT OF PSYCHIATRIC DISORDERS<br/>[FR] DÉRIVÉS DE DIAZABICYCLO[4.3.1]DÉCANE POUR LE TRAITEMENT DE TROUBLES PSYCHIATRIQUES
申请人：MAX PLANCK GES ZUR FÖRDERUNG DER WISSENSCHAFTEN E V
公开号：WO2015110271A1
公开（公告）日：2015-07-30
The present invention relates to diazabicyclo[4.3.1 ]decane derivatives (I), pharmaceutically acceptable salts of these compounds and pharmaceutical compositions containing at least one of these compounds together with pharmaceutically acceptable carrier, excipient and/or diluents. Said diazabicyclo[4.3.1]decane derivatives are specific inhibitors of the FK506 binding proteins (FKBP's) and can be used for prophylaxis and/or treatment of psychiatric disorders and neurodegenerative diseases, disorders and conditions.
Diazabicyclo[4.3.1]decane derivatives for treatment of psychiatric disorders
申请人：Max-Planck-Gesellschaft zur Förderung
der Wissenschaften e.V.
公开号：EP2899192A1
公开（公告）日：2015-07-29
The present invention relates to diazabicyclo[4.3.1]decane derivatives of formula (I), pharmaceutically acceptable salts of these compounds and pharmaceutical compositions containing at least one of these compounds together with pharmaceutically acceptable carrier, excipient and/or diluents. Said diazabicyclo[4.3.1]decane derivatives are inhibitors of the FK506 binding protein (FKBP's) and can be used for prophylaxis and/or treatment of psychiatric disorders and neurodegenerative diseases, disorders and conditions.
DIAZABICYCLO[4.3.1]DECANE DERIVATIVES FOR TREATMENT OF PSYCHIATRIC DISORDERS
申请人：MAX-PLANCK-GESELLSCHAFT ZUR FÖRDERUNG DER WISSENSCHAFTEN E.V.
公开号：US20170002003A1
公开（公告）日：2017-01-05
The present invention relates to diazabicyclo[4.3.1]decane derivatives, pharmaceutically acceptable salts of these compounds and pharmaceutical compositions containing at least one of these compounds together with pharmaceutically acceptable carrier, excipient and/or diluents. Said diazabicyclo[4.3.1]decane derivatives can be used for prophylaxis and/or treatment of psychiatric disorders and neurodegenerative diseases, disorders and conditions.
