Trazodone is heavily metabolized and activated in the liver by CYP3A4 enzyme to the active metabolite, m-chlorophenylpiperazine (mCPP). The full metabolism of trazodone has not been well characterized. Some other metabolites that have been identified are a dihydrodiol metabolite and carboxylic acid.
Trazodone is extensively metabolized in the liver via hydroxylation, oxidation, N-oxidation, and splitting of the pyridine ring. A hydroxylated metabolite and oxotriazolopyridinpropionic acid (an inactive metabolite excreted in urine) are conjugated with glucuronic acid. Results of in vitro studies indicate that metabolism of trazodone to an active metabolite, m-chlorophenylpiperazine, is mediated by the cytochrome P-450 (CYP) 3A4 isoenzyme. The manufacturers state that other metabolic pathways involved in metabolism of trazodone have not been well characterized. Results from animal studies indicate that trazodone does not induce its own metabolism.
In vitro studies in human liver microsomes show that trazodone is metabolized, via oxidative cleavage, to an active metabolite, m-chlorophenylpiperazine (mCPP) by CYP3A4. Other metabolic pathways that may be involved in the metabolism of trazodone have not been well characterized. Trazodone is extensively metabolized; less than 1% of an oral dose is excreted unchanged in the urine.
Approximately 70-75% of an oral dose of trazodone is excreted in urine within 72 hours of administration, principally as metabolites. About 20% of an oral dose of trazodone is excreted in urine as oxotriazolopyridinpropionic acid and its conjugates, and about 10% as a dihydrodiol metabolite; less than 1% of a dose is excreted unchanged. The remainder of an oral dose of the drug is excreted in feces via biliary elimination, principally as metabolites.
来源:Hazardous Substances Data Bank (HSDB)
代谢
曲唑酮已知的人类代谢物包括1-(3-氯苯基)哌嗪、对羟基曲唑酮和曲唑酮环氧化物。
Trazodone has known human metabolites that include 1-(3-Chlorophenyl)piperazine, p-Hydroxytrazodone, and Trazodone epoxide.
IDENTIFICATION AND USE: Trazodone is in the form of crystals. Trazodone hydrochloride tablets USP are indicated for the treatment of major depressive disorder (MDD) in adults. Trazodone has been used in dogs for events that trigger anxiety. HUMAN EXPOSURE AND TOXICITY: The most severe reactions reported to have occurred with overdose of trazodone alone have been priapism, respiratory arrest, seizures, and ECG changes. The reactions reported most frequently have been drowsiness and vomiting. Trazodone is known to prolong the QT/QTc interval. Some drugs that prolong the QT/QTc interval can cause Torsades de Pointes with sudden, unexplained death. A study of pregnant women who had been exposed to trazodone suggested that the drug does not increase the rate of major malformations above the baseline rate. ANIMAL STUDIES: Tremors, vomiting and clonic convulsions were produced in dogs given 50 and 100 mg/kg/day orally for one month. Administration of approximately 250 mg/kg/day in the diet of rats for 6 months resulted in significantly greater liver weights and slightly lower weight gain in males. Rats were used to conduct a two year carcinogenicity study. In both treatment groups, larger numbers of female rats died sooner than controls; most deaths were related to the presence of pituitary tumors. In both treatment groups at 12, 13 and 14 months, the incidence of palpable masses (mammary tumors, cysts, etc.) was increased also. Two developmental rat studies were conducted: one in which rats were given 100 and 210 mg/kg/day orally during days 10-15 and 6-15 of gestation, respectively; and another in which doses of 150-450 mg/kg/day were given orally during days 9-14 of gestation. Only a sedative effect on dams was noted at 100 mg/kg. Increased sedation, decreased maternal and fetal weights and retarded ossification were produced at doses of 150 mg/kg and higher. A significant increase in resorptions and stillborn fetuses, in addition to retarded fetal growth, occurred with 300 and 450 mg/kg.
Trazodone binds at 5-HT2 receptor, it acts as a serotonin agonist at high doses and a serotonin antagonist at low doses. Like fluoxetine, trazodone's antidepressant activity likely results from blockage of serotonin reuptake by inhibiting serotonin reuptake pump at the presynaptic neuronal membrane. If used for long time periods, postsynaptic neuronal receptor binding sites may also be affected. The sedative effect of trazodone is likely the result of alpha-adrenergic blocking action and modest histamine blockade at H1 receptor. It weakly blocks presynaptic alpha2-adrenergic receptors and strongly inhibits postsynaptic alpha1 receptors. Trazodone does not affect the reuptake of norepinephrine or dopamine within the CNS.
Liver test abnormalities occur in a proportion of patients on trazodone, but elevations are usually modest and usually do not require dose modification or discontinuation. At least a dozen instances of acute, clinically apparent episodes of liver injury with marked liver enzyme elevations with or without jaundice have been reported in patients on trazodone. The onset of injury varies from a few days to 6 months and the pattern of serum enzyme elevations is usually hepatocellular, but mixed and cholestatic forms have also been described. Several cases have had immunoallergic features (rash, fever, eosinophilia), but these were not prominent. Autoimmune (autoantibodies) features are uncommon. Rare instances of acute liver failure and death from trazodone have been reported. Nefazodone, an antidepressant similar in structure and mechanism of action to trazodone, was approved for use in 1998, but is currently not commonly used because of multiple reports of acute hepatocellular injury, with a high mortality rate arising 2 weeks to 6 months after starting therapy.
Trazodone is rapidly absorbed in the gastrointestinal tract after oral administration, with a bioavailability ranging from 63-91% and an AUC0−t of 18193.0 ng·h/mL. Food may impact absorption in a variable fashion, and may sometimes lead to decreases in the Cmax of trazodone. In the fed state in 8 healthy volunteers, the Cmax was measured to be 1.47 +/- 0.16 micrograms/mL, and in the fasted state, was measured at 1.88 +/- 0.42 micrograms/mL. The average Tmax after a single dose of 300 mg was 8 hours. Food may increase absorption by up to 20%.
Less than 1% of an oral dose is excreted unchanged in the urine. In a pharmacokinetic study, about 60-70% of radiolabeled was excreted urine within 48 hours. Approximately 9-29% was found to be excreted in feces over a range of 60 to 100 hours. According to the FDA medical review, the kidneys are responsible for 70 to 75% of trazodone excretion. About 21% of trazodone is reported to be excreted by the fecal route and 0.13% of the parent drug is eliminated in the urine as unchanged drug.
A single-dose pharmacokinetic study of 8 volunteers taking trazodone determined a volume of distribution of 0.84 +/- 0.16 L/kg. The FDA medical review of trazodone reports a volume of distribution of 0.47 to 0.84 L/kg.
A decrease in total apparent clearance (5.1 versus 10.8 L/h) was seen elderly volunteers in the fasted state when compared with younger volunteers. Another pharmacokinetic study determined the total body clearance of trazodone to be 5.3 +/- 0.9 L/hr in 8 healthy patients taking a single dose of trazodone.
Following oral administration of single doses of 25, 50, or 100 mg of trazodone to healthy, fasted adults in another study, mean peak plasma trazodone concentrations were 490, 860, and 1620 ng/mL, respectively. The areas under the plasma concentration-time curves (AUCs) were 3.44, 5.95, and 11.19 ug-hr/mL, for the 25-, 50-, and 100-mg doses, respectively. Limited crossover data are available comparing AUCs in fasted and nonfasted patients; however, it appears that the presence of food slightly increases the AUC for trazodone.
[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] 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.
[EN] CROSS-LINKED PYRROLOBENZODIAZEPINE DIMER (PBD) DERIVATIVE AND ITS CONJUGATES<br/>[FR] DÉRIVÉ DE DIMÈRE DE PYRROLOBENZODIAZÉPINE RÉTICULÉ (PBD) ET SES CONJUGUÉS
申请人：HANGZHOU DAC BIOTECH CO LTD
公开号：WO2020006722A1
公开（公告）日：2020-01-09
A novel cross-linked cytotoxic agents, pyrrolobenzo-diazepine dimer (PBD) derivatives, and their conjugates to a cell-binding molecule, a method for preparation of the conjugates and the therapeutic use of the conjugates.
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。
NAPHTHALENE-BASED INHIBITORS OF ANTI-APOPTOTIC PROTEINS
申请人：Pellecchia Maurizio
公开号：US20090105319A1
公开（公告）日：2009-04-23
Methods of using apogossypol and its derivatives for treating inflammation is disclosed. Also, there is described a group of compounds having structure A, or a pharmaceutically acceptable salt, hydrate, N-oxide, or solvate thereof are provided:
wherein each R is independently selected from the group consisting of H, C(O)X, C(O)NHX, NH(CO)X, SO
2
NHX, and NHSO
2
X, wherein X is selected from the group consisting of an alkyl, a substituted alkyl, an aryl, a substituted aryl, an alkylaryl, and a heterocycle. Compounds of group A may be used for treating various diseases or disorders, such as cancer.
