Absorption, Distribution and Excretion
Following oral administration of tetrabenazine, the extent of absorption is at least 75%. After single oral doses ranging from 12.5 to 50 mg, plasma concentrations of tetrabenazine are generally below the limit of detection because of the rapid and extensive hepatic metabolism of tetrabenazine. Food does not affect the absorption of tetrabenazine. Cmax, oral = 4.8 ng/mL in HD or tardive dyskinesia patients; Tmax, oral = 69 min in HD or tardive dyskinesia patients
After oral administration, tetrabenazine is extensively hepatically metabolized, and the metabolites are primarily renally eliminated (75%). Tetrabenazine is also cleared fecally (7% to 16%). Unchanged tetrabenazine has not been found in human urine. Urinary excretion of α-HTBZ or β-HTBZ (the major metabolites) accounted for less than 10% of the administered dose.
Steady State, IV, in HD or tardive dyskinesia patients: 385L. Tetrabenazine is rapidly distributed to the brain following IV injection. The site with the highest binding is the striatum, while the lowest binding was observed in the cortex.
IV, 1.67 L/min in HD or tardive dyskinesia patients
The extent of absorption is 80% with oral deutetrabenazine. As deutetrabenazine is extensively metabolized to its main active metabolites following administration, linear dose dependence of peak plasma concentrations (Cmax) and AUC was observed for the metabolites after single or multiple doses of deutetrabenazine (6 mg to 24 mg and 7.5 mg twice daily to 22.5 mg twice daily). Cmax of deuterated α-HTBZ and β-HTBZ are reached within 3-4 hours post-dosing. Food may increase the Cmax of α-HTBZ or β-HTBZ by approximately 50%, but is unlikely to have an effect on the AUC.
Deutetrabenazine is mainly excreted in the urine as metabolites. In healthy subjects, about 75% to 86% of the deutetrabenazine dose was excreted in the urine, and fecal recovery accounted for 8% to 11% of the dose. Sulfate and glucuronide conjugates of the α-HTBZ and β-HTBZ, as well as products of oxidative metabolism, accounted for the majority of metabolites in the urine. α-HTBZ and β-HTBZ metabolites accounted for less than 10% of the administered dose in the urine.
The median volume of distribution (Vc/F) of the α-HTBZ, and the β-HTBZ metabolites of deutetrabenazine are approximately 500 L and 730 L, respectively. Human PET-scans of tetrabenazine indicate rapid distribution to the brain, with the highest binding in the striatum and lowest binding in the cortex. Similar distribution pattern is expected for deutetrabenazine.
In patients with Huntington's disease, the median clearance values (CL/F) of the α-HTBZ, and the β-HTBZ metabolites of deutetrabenazine are approximately 47 L/hour and 70 L/hour, respectively.
The in vitro protein binding of tetrabenazine, alpha-dihydrotetrabenazine (a-HTBZ), and beta-dihydrotetrabenazine (b-HTBZ) was examined in human plasma for concentrations ranging from 50 to 200 ng/mL. Tetrabenazine binding ranged from 82% to 85%, a-HTBZ binding ranged from 60% to 68%, and b-HTBZ binding ranged from 59% to 63%.
Results of PET-scan studies in humans show that radioactivity is rapidly distributed to the brain following intravenous injection of (11)C-labeled tetrabenazine or alpha-dihydrotetrabenazine (a-HTBZ), with the highest binding in the striatum and lowest binding in the cortex.
Tetrabenazine or its metabolites bind to melanin-containing tissues (i.e., eye, skin, fur) in pigmented rats. After a single oral dose of radiolabeled tetrabenazine, radioactivity was still detected in eye and fur at 21 days post dosing.
In a mass balance study in 6 healthy volunteers, approximately 75% of the dose was excreted in the urine, and fecal recovery accounted for approximately 7 to 16% of the dose. Unchanged tetrabenazine has not been found in human urine.
Following oral administration of tetrabenazine, the extent of absorption is at least 75%. After single oral doses ranging from 12.5 to 50 mg, plasma concentrations of tetrabenazine are generally below the limit of detection because of the rapid and extensive hepatic metabolism of tetrabenazine by carbonyl reductase to the active metabolites alpha-dihydrotetrabenazine (a-HTBZ) and beta-dihydrotetrabenazine (b-HTBZ). a-HTBZ and b-HTBZ are metabolized principally by CYP2D6. Peak plasma concentrations (Cmax) of a-HTBZ and b-HTBZ are reached within 1 to 1 1/2 hours post-dosing. a-HTBZ is subsequently metabolized to a minor metabolite, 9-desmethyl-a-DHTBZ. b-HTBZ is subsequently metabolized to another major circulating metabolite, 9-desmethyl-b-DHTBZ, for which Cmax is reached approximately 2 hours post-dosing.
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.
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.
Austedo is primarily renally eliminated in the form of metabolites.

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Metabolism / Metabolites
Tetrabenazine is hepatically metabolized. Carbonyl reductase in the liver is responsible for the formation of two major active metabolites: α-dihydrotetrabenazine (α-HTBZ) and β-dihydrotetrabenazine (β-HTBZ). α-HTBZ is further metabolized into 9-desmethyl-α-DHTBZ, a minor metabolite by CYP2D6 and with some contribution of CYP1A2. β-HTBZ is metabolized to another major circulating metabolite, 9-desmethyl-β-DHTBZ, by CYP2D6. The Tmax of this metabolite is 2 hours post-administration of tetrabenazine.
Deutetrabenazine undergoes extensive hepatic biotransformation mediated by carbonyl reductase to form its major active metabolites, α-HTBZ and β­-HTBZ. These metabolites may subsequently metabolized to form several minor metabolites, with major contribution of CYP2D6 and minor contributions of CYP1A2 and CYP3A4/5.
In a mass balance study in 6 healthy volunteers, approximately 75% of the dose was excreted in the urine, and fecal recovery accounted for approximately 7 to 16% of the dose. Unchanged tetrabenazine has not been found in human urine. Urinary excretion of alpha-dihydrotetrabenazine (a-HTBZ) or beta-dihydrotetrabenazine (b-HTBZ) accounted for less than 10% of the administered dose. Circulating metabolites, including sulfate and glucuronide conjugates of HTBZ metabolites as well as products of oxidative metabolism, account for the majority of metabolites in the urine.
After oral administration, tetrabenazine is extensively hepatically metabolized, and the metabolites are primarily renally eliminated.
The results of in vitro studies do not suggest that tetrabenazine, alpha-dihydrotetrabenazine (a-HTBZ), beta-dihydrotetrabenazine (b-HTBZ) or 9-desmethyl-beta-dihydrotetrabenazine are likely to result in clinically significant inhibition of CYP2D6, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2E1, or CYP3A. In vitro studies suggest that neither tetrabenazine nor its a- or b-HTBZ or 9-desmethyl-beta-dihydrotetrabenazine metabolites are likely to result in clinically significant induction of CYP1A2, CYP3A4, CYP2B6, CYP2C8, CYP2C9, or CYP2C19.
After oral administration in humans, at least 19 metabolites of tetrabenazine have been identified. alpha-Dihydrotetrabenazine (a-HTBZ), beta-dihydrotetrabenazine (b-HTBZ) and 9-desmethyl-beta-dihydrotetrabenazine are the major circulating metabolites and are subsequently metabolized to sulfate or glucuronide conjugates. a-HTBZ and b-HTBZ are formed by carbonyl reductase that occurs mainly in the liver. a-HTBZ is O-dealkylated by CYP450 enzymes, principally CYP2D6, with some contribution of CYP1A2 to form 9-desmethyl-alpha-dihydrotetrabenazine, a minor metabolite. b-HTBZ is O-dealkylated principally by CYP2D6 to form 9-desmethyl-beta-dihydrotetrabenazine.
Following oral administration of tetrabenazine, the extent of absorption is at least 75%. After single oral doses ranging from 12.5 to 50 mg, plasma concentrations of tetrabenazine are generally below the limit of detection because of the rapid and extensive hepatic metabolism of tetrabenazine by carbonyl reductase to the active metabolites alpha-dihydrotetrabenazine (a-HTBZ) and beta-dihydrotetrabenazine (b-HTBZ). a-HTBZ and b-HTBZ are metabolized principally by CYP2D6. Peak plasma concentrations (Cmax) of a-HTBZ and b-HTBZ are reached within 1 to 1 1/2 hours post-dosing. a-HTBZ is subsequently metabolized to a minor metabolite, 9-desmethyl-a-DHTBZ. b-HTBZ is subsequently metabolized to another major circulating metabolite, 9-desmethyl-b-DHTBZ, for which Cmax is reached approximately 2 hours post-dosing.
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.

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Biological Half-Life
There is interindividual variability in elimination half-life. The elimination half-life of tetrabenazine was 10 hours following intravenous bolus administration. The oral half-lives of its metabolites, α-HTBZ, β-HTBZ and 9-desmethyl-β-DHTBZ, are seven hours, five hours and 12 hours, respectively. Following a single oral dose of 25 mg tetrabenazine, the elimination half-life was approximately 17.5 hours in subjects with hepatic impairment.
The half-life of total (α+β)-HTBZ from deutetrabenazine is approximately 9 to 10 hours.
alpha-Dihydrotetrabenazine (a-HTBZ), beta-dihydrotetrabenazine (b-HTBZ) and 9-desmethyl-beta-dihydrotetrabenazine have half-lives of 7 hours, 5 hours and 12 hours respectively. /Tetrabenazine metabolites/
The half-life of total (alpha+beta)-dihydrotetrabenazine from deutetrabenazine is approximately 9 to 10 hours.

Toxicity Summary
IDENTIFICATION AND USE: Tetrabenazine is a solid. It is used as adrenergic uptake inhibitor for the treatment of chorea associated with Huntington's disease. Pharmacology studies demonstrate that betrabenzaine reversibly inhibits the activity of vesicular monoamine transporter 2, resulting in depletion of central dopamine. HUMAN STUDIES: Adverse effects are dose and age related and include depression, fatigue, parkinsonism, and somnolence. Neuroleptic malignant syndrome (NMS), a potentially fatal syndrome, has been reported in patients receiving tetrabenazine and other drugs that reduce dopaminergic transmission. Three episodes of overdose occurred in the open-label trials performed in support of registration. Eight cases of overdose have been reported in the literature. The dose of the drug in these patients ranged from 100 mg to 1 g. Adverse reactions associated with overdose include acute dystonia, oculogyric crisis, nausea and vomiting, sweating, sedation, hypotension, confusion, diarrhea, hallucinations, rubor, and tremor. Completed suicide, attempted suicide, and 6 cases of suicidal ideation were reported in 187 tetrabenazine recipients. Major human metabolite 9-Desmethyl-beta-dihydrotetrabenazine was not clastogenic in an in vitro chromosomal aberration assay in human peripheral blood mononuclear cells in the presence or absence of metabolic activation. ANIMAL STUDIES: No increase in tumors was observed in transgenic mice treated orally with a major human metabolite, 9-desmethyl-beta-dihydrotetrabenazine (20, 100, and 200 mg/kg/day), for 26 weeks. Oral administration of tetrabenazine (5, 15, or 30 mg/kg/day) to female rats prior to and throughout mating, and continuing through day 7 of gestation resulted in disrupted estrous cyclicity at doses greater than 5 mg/kg/day. No effects on mating and fertility indices or sperm parameters (motility, count, density) were observed when male rats were treated orally with tetrabenazine (5, 15, or 30 mg/kg/day. However, because rats dosed with tetrabenazine do not produce 9-desmethyl-beta-dihydrotetrabenazine, a major human metabolite, this study may not have adequately assessed the potential of the drug to impair fertility in humans. Oral administration of 9-desmethyl-beta-dihydrotetrabenazine (8, 15, and 40 mg/kg/day) to pregnant and lactating rats throughout the period of organogenesis produced increases in embryofetal mortality at 15 and 40 mg/kg/day and reductions in fetal body weights at 40 mg/kg/day, which was also maternally toxic. When 9-desmethyl-beta-dihydrotetrabenazine (8, 15, and 40 mg/kg/day) was orally administered to pregnant rats from the beginning of organogenesis through the lactation period, increases in gestation duration, stillbirths, and offspring postnatal mortality (40 mg/kg/day); decreases in pup weights (40 mg/kg/day); and neurobehavioral (increased activity, learning and memory deficits) and reproductive (decreased litter size) impairment (15 and 40 mg/kg/day) were observed. Maternal toxicity was seen at the highest dose. Tetrabenazine and metabolites alpha-dihydrotetrabenazine (a-HTBZ), beta-dihydrotetrabenazine (b-HTBZ), and 9-desmethyl-beta-dihydrotetrabenazine were negative in an in vitro bacterial reverse mutation assay. Tetrabenazine was clastogenic in an in vitro chromosomal aberration assay in Chinese hamster ovary cells in the presence of metabolic activation. a-HTBZ and b-HTBZ were clastogenic in an in vitro chromosome aberration assay in Chinese hamster lung cells in the presence and absence of metabolic activation. In vivo micronucleus assays were conducted in male and female rats and male mice. Tetrabenazine was negative in male mice and rats but produced an equivocal response in female rats.
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.

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Hepatotoxicity
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.
Likelihood score: E (unlikely cause of clinically apparent liver injury).

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Protein Binding
Tetrabenazine = 82 - 88%; α-HTBZ = 60 - 68%; β-HTBZ = 59 - 63%.
At doses ranging from 50 to 200 ng/mL _in vitro_, tetrabenazine protein binding ranged from 82% to 85%, α-HTBZ binding ranged from 60% to 68%, and β-HTBZ binding ranged from 59% to 63%. Similar protein binding pattern is expected for deutetrabenazine and its metabolites.

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Interactions
We herein describe the case of an 81-year-old Japanese woman with neuroleptic malignant syndrome that occurred 36 days after the initiation of combination therapy with tiapride (75 mg/day) and tetrabenazine (12.5 mg/day) for Huntington's disease. The patient had been treated with tiapride or tetrabenazine alone without any adverse effects before the administration of the combination therapy. She also had advanced breast cancer when the combination therapy was initiated. To the best of our knowledge, the occurrence of neuroleptic malignant syndrome due to combination therapy with tetrabenazine and tiapride has not been previously reported. Tetrabenazine should be administered very carefully in combination with other neuroleptic drugs, particularly in patients with a worsening general condition.
The efficacy of the dopaminergic stabilizer, pridopidine, in reducing the voluntary and involuntary motor symptoms of Huntington's disease (HD) is under clinical evaluation. Tetrabenazine is currently the only approved treatment for chorea, an involuntary motor symptom of HD; both compounds influence monoaminergic neurotransmission. /The objective of the study was/ to investigate pharmacological interactions between pridopidine and tetrabenazine. Drug-interaction experiments, supplemented by dose-response data, examined the effects of these compounds on locomotor activity, on striatal levels of dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC), and on levels of activity-regulated cytoskeleton-associated (Arc) gene expression in the striatum and frontal cortex of male Sprague-Dawley rats. Haloperidol, a classical dopamine D2 receptor antagonist, was also tested for comparison. Monitoring for 1 hour after co-administration of tetrabenazine 0.64 mg/kg and pridopidine 32 mg/kg revealed a reduction in locomotor activity, measured as distance travelled, in the tetrabenazine treated group, down to 61% vs. vehicle controls (p < 0.001). This was significantly alleviated by pridopidine (distance travelled reached 137% vs. tetrabenazine controls, p < 0.01). In contrast, co-administration of haloperidol 0.12 mg/kg and tetrabenazine produced increased inhibition of locomotor activity over the same period (p < 0.01, 41% vs. tetrabenazine). Co-administration of pridopidine, 10.5 mg/kg or 32 mg/kg, with tetrabenazine counteracted significantly (p < 0.05) and dose-dependently the decrease in frontal cortex Arc levels induced by tetrabenazine 0.64 mg/kg (Arc mRNA reached 193% vs. tetrabenazine mean at 32 mg/kg); this counteraction was not seen with haloperidol. Tetrabenazine retained its characteristic neurochemical effects of increased striatal DOPAC and reduced striatal dopamine when co-administered with pridopidine. Pridopidine alleviates tetrabenazine-induced behavioural inhibition in rats. This effect may be associated with pridopidine-induced changes in cortical activity and may justify clinical evaluation of pridopidine/tetrabenazine combination therapy.
The risk for Parkinsonism, neuroleptic malignant syndrome (NMS), and akathisia may be increased by concomitant use of Xenazine and dopamine antagonists or antipsychotics (e.g., chlorpromazine, haloperidol, olanzapine, risperidone, thioridazine, ziprasidone)
Potential pharmacologic interaction (serotonin and norepinephrine depletion in the CNS). Concomitant therapy is contraindicated. Clinicians should wait for signs of chorea to re-emerge after discontinuing reserpine before initiating tetrabenazine therapy. At least 20 days should elapse after reserpine discontinuance prior to initiating tetrabenazine therapy.
For more Interactions (Complete) data for Tetrabenazine (12 total), please visit the HSDB record page.
Austedo is contraindicated in patients currently taking tetrabenazine or valbenazine. Austedo may be initiated the day following discontinuation of tetrabenazine
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.
Austedo is contraindicated in patients taking monoamine oxidase inhibitors (MAOIs). Austedo should not be used in combination with an MAOI, or within 14 days of discontinuing therapy with an MAOI.
For more Interactions (Complete) data for Deutetrabenazine (6 total), please visit the HSDB record page.

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Non-Human Toxicity Values
LD50 Mouse iv 150 mg/kg
LD50 Mouse sc 400 mg/kg
LD50 Mosue ip 250 mg/kg
LD50 Mouse oral 550 mg/kg

[1]. Effort-related motivational effects of the VMAT-2 inhibitor tetrabenazine: implications for animal models of the motivational symptoms of depression. J Neurosci. 2013 Dec 4;33(49):19120-30.

[2]. The vesicular monoamine transporter (VMAT-2) inhibitor tetrabenazine induces tremulous jaw movements in rodents: implications for pharmacological models of parkinsonian tremor. Neuroscience. 2013 Oct 10;250:507-19.

[3]. Tetrabenazine, an amine-depleting drug, also blocks dopamine receptors in rat brain. J Pharmacol Exp Ther. 1983 Jun;225(3):515-21.

9,10-dimethoxy-3-isobutyl-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one is a benzoquinolizine that is 1,2,3,4,4a,9,10,10a-octahydrophenanthrene in which the carbon at position 10a is replaced by a nitrogen and which is substituted by an isobutyl group at position 2, an oxo group at position 3, and methoxy groups at positions 6 and 7. It is a benzoquinolizine, a cyclic ketone and a tertiary amino compound.
A drug formerly used as an antipsychotic but now used primarily in the symptomatic treatment of various hyperkinetic disorders. It is a monoamine depletor and used as symptomatic treatment of chorea associated with Huntington's disease. FDA approved on August 15, 2008.
Deutetrabenazine is a novel, highly selective vesicular monoamine transporter 2 (VMAT2) inhibitor indicated for the management of chorea associated with Huntington’s disease. It is a hexahydro-dimethoxybenzoquinolizine derivative and a deuterated [DB04844]. The presence of deuterium in deutetrabenazine increases the half-lives of the active metabolite and prolongs their pharmacological activity by attenuating CYP2D6 metabolism of the compound. This allows less frequent dosing and a lower daily dose with improvement in tolerability. Decreased plasma fluctuations of deutetrabenazine due to attenuated metabolism may explain a lower incidence of adverse reactions associated with deutetrabenazine. Deutetrabenazine is a racemic mixture containing RR-Deutetrabenazine and SS-Deutetrabenazine. Huntington's disease (HD) is a hereditary, progressive neurodegenerative disorder characterized by motor dysfunction, cognitive decline, and neuropsychiatric disturbances that interfere with daily functioning and significantly reduce the quality of life. The most prominent physical symptom of HD that may increase the risk of injury is chorea, which is an involuntary, sudden movement that can affect any muscle and flow randomly across body regions. Psychomotor symptoms of HD, such as chorea, are related to hyperactive dopaminergic neurotransmission. Deutetrabenazine depletes the levels of presynaptic dopamine by blocking VMAT2, which is responsible for the uptake of dopamine into synaptic vesicles in monoaminergic neurons and exocytotic release. As with other agents for the treatment of neurodegenerative diseases, deutetrabenazine is a drug to alleviate the motor symptoms of HD and is not proposed to halt the progression of the disease. In clinical trials of patients with HD, 12 weeks of treatment of deutetrabenazine resulted in overall improvement in mean total maximal chorea scores and motor signs than placebo. It was approved by FDA in April 2017 and is marketed under the trade name Austedo as oral tablets.
The vesicular monoamine transporter type 2 (VMAT2) inhibitors are agents that cause a depletion of neuroactive peptides such as dopamine in nerve terminals and are used to treat chorea due to neurodegenerative diseases (such as Huntington chorea) or dyskinesias due to neuroleptic medications (tardive dyskinesia). As of 2019, three VMAT2 inhibitors have become available in the United States for management of dyskinesia syndromes, each with a somewhat different spectrum of approved indications: tetrabenazine (Xenazine and generics: 2008), deutetrabenazine (Austedo: 2017) and valbenazine (Ingressa: 2017). The VMAT2 inihibitors have not been associated with serum enzyme elevations during therapy or linked to instances of clinically apparent liver injury, but they have had limited general clinical use.
A drug formerly used as an antipsychotic and treatment of various movement disorders. Tetrabenazine blocks neurotransmitter uptake into adrenergic storage vesicles and has been used as a high affinity label for the vesicle transport system.
See also: Tetrabenazine Methanesulfonate (has salt form).

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Drug Indication
Treatment of hyperkinetic movement disorders like chorea in Huntington's disease, hemiballismus, senile chorea, Tourette syndrome and other tic disorders, and tardive dyskinesia
FDA Label
Deutetrabenazine is indicated in adults patients for the treatment of tardive dyskinesia and for chorea associated with Huntington's disease.

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Mechanism of Action
Tetrabenazine is a reversible human vesicular monoamine transporter type 2 inhibitor (Ki = 100 nM). It acts within the basal ganglia and promotes depletion of monoamine neurotransmitters serotonin, norepinephrine, and dopamine from stores. It also decreases uptake into synaptic vesicles. Dopamine is required for fine motor movement, so the inhibition of its transmission is efficacious for hyperkinetic movement. Tetrabenazine exhibits weak in vitro binding affinity at the dopamine D2 receptor (Ki = 2100 nM).
The precise mechanism of action of deutetrabenazine in mediating its anti-chorea effects is not fully elucidated. Deutetrabenazine reversibly depletes the levels of monoamines, such as dopamine, serotonin, norepinephrine, and histamine, from nerve terminals via its active metabolites. The major circulating metabolites are α-dihydrotetrabenazine [HTBZ] and β-HTBZ that act as reversible inhibitors of VMAT2. Inhibition of VMAT2 results in decreased uptake of monoamines into synaptic terminal and depletion of monoamine stores from nerve terminals. Deutetrabenazine contains the molecule deuterium, which is a naturally-occurring, nontoxic hydrogen isotope but with an increased mass relative to hydrogen. Placed at key positions, deuterium forms a stronger hydrogen bond with carbon that requires more energy for cleavage, thus attenuating CYP2D6-mediated metabolism without having any effect on the therapeutic target.
... Pharmacology studies demonstrate that betrabenzaine reversibly inhibits the activity of vesicular monoamine transporter 2, resulting in depletion of central dopamine. ...

C19H27NO3

317.4226

317.199

718635-93-9

Tetrabenazine;58-46-8;(+)-Tetrabenazine;1026016-83-0;Tetrabenazine-d6;1392826-25-3

6018

Light yellow to yellow solid powder

3.176

0

4

4

23

425

0

MKJIEFSOBYUXJB-UHFFFAOYSA-N

InChI=1S/C19H27NO3/c1-12(2)7-14-11-20-6-5-13-8-18(22-3)19(23-4)9-15(13)16(20)10-17(14)21/h8-9,12,14,16H,5-7,10-11H2,1-4H3

9,10-dimethoxy-3-(2-methylpropyl)-1,3,4,6,7,11b-hexahydrobenzo[a]quinolizin-2-one

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~50 mg/mL (~157.52 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (7.88 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: 2.5 mg/mL (7.88 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (7.88 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)