In a mass balance study in 6 healthy subjects, 75% to 86% of the deutetrabenazine dose was excreted in the urine, and fecal recovery accounted for 8% to 11% of the dose. Urinary excretion of the alpha-dihydrotetrabenazine and beta-dihydrotetrabenazine metabolites from deutetrabenazine each accounted for less than 10% of the administered dose. Sulfate and glucuronide conjugates of the alpha-dihydrotetrabenazine and beta-dihydrotetrabenazine metabolites of deutetrabenazine, as well as products of oxidative metabolism, accounted for the majority of metabolites in the urine.
In vitro experiments in human liver microsomes demonstrate that deutetrabenazine is extensively biotransformed, mainly by carbonyl reductase, to its major active metabolites, alpha-dihydrotetrabenazine and beta-dihydrotetrabenazine, which are subsequently metabolized primarily by CYP2D6, with minor contributions of CYP1A2 and CYP3A4/5, to form several minor metabolites.
IDENTIFICATION AND USE: Deutetrabenazine is used as adrenergic uptake inhibitor. It is is indicated for the treatment of chorea associated with Huntington's disease (HD) and tardive dyskinesia in adults. HUMAN STUDIES: Overdoses ranging from 100 mg to 1 g have been reported in the literature with tetrabenazine, a closely related vesicular monoamine transporter 2 (VMAT2) inhibitor. The following adverse reactions occurred with overdosing: acute dystonia, oculogyric crisis, nausea and vomiting, sweating, sedation, hypotension, confusion, diarrhea, hallucinations, rubor, and tremor. Indirect treatment comparison demonstrates that for the treatment of HD chorea, deutetrabenazine has a favorable tolerability profile compared to tetrabenazine. Deutetrabenazine may increase the risk for suicidality in patients with HD. Deutetrabenazine should be avoided in patients with congenital long QT syndrome and in patients with a history of cardiac arrhythmias. Deutetrabenazine and its deuterated alpha-dihydrotetrabenazine and beta-dihydrotetrabenazine metabolites were negative in in vitro chromosome aberration assay in human peripheral blood lymphocytes in the presence or absence of metabolic activation. ANIMAL STUDIES: Oral administration of deutetrabenazine (5, 10, or 30 mg/kg/day) to pregnant rats during organogenesis had no clear effect on embryofetal development. Oral administration of deutetrabenazine (doses of 5, 10, or 30 mg/kg/day) to female rats for 3 months resulted in estrous cycle disruption at all doses. Deutetrabenazine and its deuterated alpha-dihydrotetrabenazine and beta-dihydrotetrabenazine metabolites were negative in in vitro bacterial reverse mutation assay in the presence or absence of metabolic activation and in the in vivo micronucleus assay in mice.
Tetrabenazine has not been associated with rates of serum enzyme elevations greater than occur with placebo therapy, but information on liver test results during therapy is limited and occasional instances of asymptomatic ALT elevations leading to drug discontinuation or dose modification have been reported by the sponsor. In prelicensure pivotal registration trials in several hundred patients, tetrabenazine was not associated with cases of jaundice or hepatitis. Since licensure, there have been no published reports of clinically apparent liver injury, jaundice or hepatitis attributed to tetrabenazine. Thus, clinically apparent liver injury with jaundice due to tetrabenazine must be rare, if it occurs at all.
Austedo is contraindicated in patients currently taking tetrabenazine or valbenazine. Austedo may be initiated the day following discontinuation of tetrabenazine
来源:Hazardous Substances Data Bank (HSDB)
毒理性
相互作用
酒精或其他镇静药物的同时使用可能会产生叠加效果，加重镇静和嗜睡症状。
Concomitant use of alcohol or other sedating drugs may have additive effects and worsen sedation and somnolence.
The risk of parkinsonism, neuroleptic malignant syndrome (NMS), and akathisia may be increased by concomitant use of Austedo and dopamine antagonists or antipsychotics.
Results of PET-scan studies in humans show that following intravenous injection of (11)C-labeled tetrabenazine or alpha-dihydrotetrabenazine, radioactivity is rapidly distributed to the brain, with the highest binding in the striatum and lowest binding in the cortex.
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
口服氘替巴比妥后，其吸收程度至少为80%。
Following oral administration of deutetrabenazine, the extent of absorption is at least 80%.
In a mass balance study in 6 healthy subjects, 75% to 86% of the deutetrabenazine dose was excreted in the urine, and fecal recovery accounted for 8% to 11% of the dose. Urinary excretion of the alpha-dihydrotetrabenazine and beta-dihydrotetrabenazine metabolites from deutetrabenazine each accounted for less than 10% of the administered dose. Sulfate and glucuronide conjugates of the alpha-dihydrotetrabenazine and beta-dihydrotetrabenazine metabolites of deutetrabenazine, as well as products of oxidative metabolism, accounted for the majority of metabolites in the urine.
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
Austedo主要以代谢物的形式通过肾脏消除。
Austedo is primarily renally eliminated in the form of metabolites.
[EN] PROCESS FOR PREPARATION OF ((3R,11BR)-1,3,4,6,7,11B-HEXAHYDRO-9,10-DI(METHOXY-D 3)-3-(2-METHYLPROPYL)-2H-BENZO[A]QUINOLIZIN-2-ONE [FR] PROCÉDÉ DE PRÉPARATION DE ((3R, 11BR) -1,3,4,6,7,11B-HEXAHYDRO-9,10-DI(MÉTHOXY-D 3)-3-(2-MÉTHYLPROPYL)-2H-BENZO[A]QUINOLIZIN-2-ONE
[EN] BENZOQUINOLINE INHIBITORS OF VESICULAR MONOAMINE TRANSPORTER 2<br/>[FR] INHIBITEURS BENZOQUINOLINE DU TRANSPORTEUR DE MONOAMINE VÉSICULAIRE 2
申请人：AUSPEX PHARMACEUTICALS INC
公开号：WO2015077521A1
公开（公告）日：2015-05-28
The present invention relates to new benzoquinoline inhibitors of vesicular monoamine transporter 2 (VMAT2), pharmaceutical compositions thereof, and methods of use thereof. (I)
本发明涉及新的囊泡单胺转运体2（VMAT2）苯并喹啉抑制剂，其制药组合物以及使用方法。
[EN] METHODS OF TREATING ABNORMAL MUSCULAR ACTIVITY<br/>[FR] MÉTHODES DE TRAITEMENT D'UNE ACTIVITÉ MUSCULAIRE ANORMALE
申请人：AUSPEX PHARMACEUTICALS INC
公开号：WO2015077520A1
公开（公告）日：2015-05-28
Methods for treating abnormal muscular activity are disclosed. The methods may be performed remotely and permit monitoring of a subject outside a healthcare provider's office.
公开了治疗异常肌肉活动的方法。这些方法可以远程进行，并允许在医疗保健提供者办公室之外监测受试者。
METHODS OF MANUFACTURING BENZOQUINOLINE COMPOUNDS
申请人：Auspex Pharmaceuticals, Inc.
公开号：US20150152099A1
公开（公告）日：2015-06-04
The present invention relates to new methods of manufacturing benzoquinoline inhibitors of vesicular monoamine transporter 2 (VMAT2), and intermediates thereof.
本发明涉及制备囊泡单胺转运体2（VMAT2）苯并喹啉抑制剂的新方法及其中间体。
Formulations and pharmacokinetics of deuterated benzoquinoline inhibitors of vesicular monoamine transporter 2
申请人：AUSPEX PHARMACEUTICALS, INC.
公开号：US11033540B2
公开（公告）日：2021-06-15
The present invention relates to new pharmaceutical compositions comprising benzoquinoline compounds, and methods to inhibit vesicular monoamine transporter 2 (VMAT2) activity in a subject for the treatment of chronic hyperkinetic movement disorders.
FORMULATIONS PHARMACOKINETICS OF DEUTERATED BENZOQUINOLINE INHIBITORS OF VESICULAR MONOAMINE TRANSPORTER 2
申请人：Auspex Pharmaceuticals, Inc.
公开号：US20140336386A1
公开（公告）日：2014-11-13
The present invention relates to new pharmaceutical compositions comprising benzoquinoline compounds, and methods to inhibit vesicular monoamine transporter 2 (VMAT2) activity in a subject for the treatment of chronic hyperkinetic movement disorders.
