Drug compounds have been modified to include stable heavy isotopes of carbon, hydrogen, and other elements, mostly as tracers that influence quantification during the drug development process. It's possible that the pharmacokinetics and functional range of medications contribute to the concern of mutagenesis. [1]. Possible benefits of compounds with delayed generation: (1) One possible benefit of delayed-generation compounds is that they may be able to extend the compound's pharmacokinetic properties. Potential benefits of compounds with delayed generation: (1) Compounds with delayed generation could be It can extend a compound's pharmacokinetic properties, extending its safety, tolerability, and ability to withstand adverse reactions in delayed-generation drugs. Enhance intestinal absorption. Deuterated compounds have the potential to decrease the level of first-pass metabolism required in the intestinal wall and colon, which would enable a higher percentage of the medicine to remain unmetabolized and achieve high bioavailability levels. These levels define the drug's efficacy at low dosages and improve its tolerability. Enhance the properties of metabolism. medication safety, medication metabolism, and toxic or reactive metabolite reduction are all potential benefits of metabolites (4). Deuterated chemicals are harmless and have the potential to lessen or eliminate the negative effects of medicinal compounds. (5) Preserve their medicinal qualities. According to earlier research, deuterated chemicals ought to maintain comparable effects and biochemical efficacy to their hydrogen counterparts.

Absorption, Distribution and Excretion
The oral absorption rate of deuterated butylbenazine is 80%. Since deuterated butylbenazine is extensively metabolized to its major active metabolite after administration, a linear dose-dependent peak plasma concentration (Cmax) and AUC of the metabolite are observed after single or multiple doses (6 mg to 24 mg and twice daily 7.5 mg to 22.5 mg). The Cmax of deuterated α-HTBZ and β-HTBZ is reached within 3–4 hours after administration. Food can increase the Cmax of α-HTBZ or β-HTBZ by approximately 50%, but is unlikely to affect AUC. Deuterated butylbenazine is primarily excreted in the urine as metabolites. In healthy subjects, approximately 75% to 86% of the deuterated butylbenazine dose is excreted in the urine, with fecal recovery accounting for 8% to 11% of the total dose. Sulfate and glucuronide conjugates of α-HTBZ and β-HTBZ, as well as oxidative metabolites, are the main components of urinary metabolites. The urinary concentration of α-HTBZ and β-HTBZ metabolites is less than 10% of the administered dose. The median volume of distribution (Vc/F) of the α-HTBZ and β-HTBZ metabolites of deuterated butylbenazine is approximately 500 L and 730 L, respectively. Human PET scans show that butylbenazine rapidly distributes to the brain, with the highest binding rate in the striatum and the lowest in the cortex. A similar distribution pattern is expected for deuterated butylbenazine. In patients with Huntington's disease, the median clearance (CL/F) of the deuterated butylbenazine metabolites α-HTBZ and β-HTBZ is approximately 47 L/h and 70 L/h, respectively.
Human PET scan studies showed that after intravenous injection of 11C-labeled butylbenazine or α-dihydrobutylbenazine, the radioactive material rapidly distributed to the brain, with the highest binding rate in the striatum and the lowest in the cortex.
Oral administration of deuterated butylbenazine resulted in an absorption rate of at least 80%.
In a mass balance study of six healthy subjects, 75% to 86% of the deuterated butylbenazine dose was excreted in the urine, with fecal recovery accounting for 8% to 11% of the total dose. The urinary excretion of the deuterated butylbenazine metabolites α-dihydrobutylbenazine and β-dihydrobutylbenazine was less than 10% of the administered dose. The sulfate and glucuronide conjugates of the deuterated butylbenazine metabolites α-dihydrobutylbenazine and β-dihydrobutylbenazine, as well as oxidative metabolites, constituted the major portion of the metabolites in the urine.
Osterdol is primarily excreted via the kidneys as metabolites.

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Metabolisms/Metabolites
Deuterated butylbenazine undergoes extensive biotransformation in the liver under the catalysis of carbonyl reductases, forming its major active metabolites α-HTBZ and β-HTBZ. These metabolites may be further metabolized to form several minor metabolites, with CYP2D6 playing a major role and CYP1A2 and CYP3A4/5 playing minor roles.
In a mass balance study of six healthy subjects, 75% to 86% of the dose of deuterated butylbenazine was excreted in the urine, with fecal recovery rates ranging from 8% to 11% of the administered dose. The urinary excretion of α-dihydrobutylbenazine and β-dihydrobutylbenazine metabolites was less than 10% of the administered dose. The sulfate and glucuronide conjugates of the deuterated butylbenazine metabolites α-dihydrobutylbenazine and β-dihydrobutylbenazine, as well as oxidative metabolites, constitute the majority of the metabolites in the urine.
In vitro human liver microsomal experiments showed that deuterated butylbenazine undergoes extensive biotransformation primarily via carbonyl reductases, generating its main active metabolites α-dihydrobutylbenazine and β-dihydrobutylbenazine. Subsequently, it is mainly metabolized by CYP2D6, with smaller contributions from CYP1A2 and CYP3A4/5, generating several minor metabolites.
Biological Half-Life
The half-life of deuterated butylbenazine to total (α+β)-HTBZ is approximately 9 to 10 hours.
The reaction time for the total (α+β)-dihydrobutylbenazine to be prepared from deuterated butylbenazine is approximately 9 to 10 hours.

Toxicity Summary
Identification and Uses: Deuterated butylbenazine is an adrenergic reuptake inhibitor. It is indicated for the treatment of chorea and tardive dyskinesia associated with Huntington's disease (HD) in adults. Human Studies: Literature reports adverse reactions from overdose of 100 mg to 1 g of deuterated butylbenazine (a closely associated vesicular monoamine transporter 2 (VMAT2) inhibitor). Adverse reactions following overdose include: acute dystonia, oculomotor crisis, nausea and vomiting, sweating, sedation, hypotension, confusion, diarrhea, hallucinations, skin flushing, and tremor. Indirect Treatment Comparisons: Deuterated butylbenazine is well-tolerated compared to butylbenazine in the treatment of chorea in HD. Deuterated butylbenazine may increase the risk of suicide in patients with HD. Deuterated butylbenazine should be avoided in patients with congenital long QT syndrome and those with a history of arrhythmias. In in vitro human peripheral blood lymphocyte chromosome aberration assays, deuterated butylbenazine and its deuterated α-dihydrobutylbenazine and β-dihydrobutylbenazine metabolites were negative regardless of metabolic activation. Animal studies: During organogenesis, oral administration of deuterated butylbenazine (5, 10, or 30 mg/kg/day) to pregnant rats had no significant effect on embryonic development. Oral administration of deuterated butylbenazine (at doses of 5, 10, or 30 mg/kg/day) to female rats for 3 months resulted in estrous cycle disturbances at all doses. Deuterated butylbenazine and its deuterated α-dihydrobutylbenazine and β-dihydrobutylbenazine metabolites were negative in in vitro bacterial reverse mutation assays (regardless of metabolic activation) and in vivo micronucleus assays in mice. Protein Binding In vitro, at doses ranging from 50 to 200 ng/mL, the protein binding rates of bubenazine are 82% to 85%, α-dihydrobubenazine is 60% to 68%, and β-dihydrobubenazine is 59% to 63%. The protein binding patterns of deuterated bubenazine and its metabolites are expected to be similar. Interactions Austeredo is contraindicated in patients taking bubenazine or valproic acid. Austeredo can be started the day after discontinuing bubenazine. Concomitant use of alcohol or other sedatives may have an additive effect, exacerbating sedation and drowsiness. Concomitant use of Austeredo with dopamine antagonists or antipsychotics may increase the risk of Parkinson's syndrome, neuroleptic malignancy (NMS), and akathisia. Austeredo is contraindicated in patients taking monoamine oxidase inhibitors (MAOIs). Osterol should not be used in combination with MAOIs, nor should it be used within 14 days after discontinuation of MAOIs. For more complete data on drug interactions of deuterated benzodiazepines (6 in total), please visit the HSDB records page.

The Lancet. 2017,4(8): 595–604.

Deutetrabenazine is a novel, highly selective vesicular monoamine transporter 2 (VMAT2) inhibitor indicated for the treatment of Huntington's disease-associated chorea. It is a hexahydrodimethoxybenzoquinolone derivative, deuterated [DB04844]. The presence of deuterium in Deutetrabenazine prolongs the half-life of the active metabolite and extends its pharmacological activity by attenuating CYP2D6 metabolism of the compound. This results in a lower dosing frequency, a smaller daily dose, and improved tolerability. The reduced plasma concentration fluctuations of Deutetrabenazine due to attenuated metabolism may explain its lower incidence of adverse reactions. Deutetrabenazine is a racemic mixture comprising 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 life and significantly reduce quality of life. The most prominent physical symptom of Huntington's disease (HD) is chorea, an involuntary, sudden movement that can affect any muscle and occurs randomly in various parts of the body, potentially increasing the risk of injury. Psychomotor symptoms of HD, such as chorea, are associated with overactive dopaminergic neurotransmission. Deuterated benzonazine reduces presynaptic dopamine levels by blocking VMAT2, which is responsible for the uptake of dopamine by monoaminergic neurons into synaptic vesicles and subsequent exocytosis. Like other medications used to treat neurodegenerative diseases, deuterated benzonazine is intended to alleviate motor symptoms of HD and not to halt disease progression. In clinical trials of Huntington's disease patients, after 12 weeks of treatment with deuterated benzonazine, patients showed significant improvements in mean total maximum chorea score and motor symptoms compared to the placebo group. The drug was approved by the FDA in April 2017 and marketed under the brand name Austedo as an oral tablet.
See also: Deuterated benzonazine (Note moved here). Drug Indications Deuterated butylbenazine is indicated for the treatment of tardive dyskinesia and Huntington's disease-related chorea in adult patients. Mechanism of Action The exact mechanism by which deuterated butylbenazine exerts its antichorea effect is not fully understood. Deuterated butylbenazine reversibly reduces the levels of monoamine neurotransmitters (such as dopamine, serotonin, norepinephrine, and histamine) in nerve endings through its active metabolites. The main circulating metabolites are α-dihydrobutylbenazine [HTBZ] and β-HTBZ, which act as reversible inhibitors of VMAT2. Inhibition of VMAT2 leads to reduced uptake of monoamine neurotransmitters at synaptic terminals and depletion of monoamine neurotransmitter stores in nerve endings. Deuterated butylbenazine contains a deuterium molecule, a naturally occurring, non-toxic hydrogen isotope with a mass greater than hydrogen. Deuterium occupies a critical position, forming stronger hydrogen bonds with carbon that require more energy to break, thus weakening CYP2D6-mediated metabolism without affecting the therapeutic target.

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Therapeutic Use
Adrenergic Uptake Inhibitors
/Clinical Trials/ ClinicalTrials.gov is a registry and outcomes database that lists human clinical studies funded by public and private sources worldwide. The website is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each record on ClinicalTrials.gov provides summary information on the study protocol, including: the disease or condition; the intervention (e.g., the medical product, behavior, or procedure under investigation); the title, description, and design of the study; participation requirements (eligibility criteria); the location where the study is conducted; contact information for the study location; and links to relevant information from other health websites, such as the NLM's MedlinePlus (which provides patient health information) and PubMed (which provides citations and abstracts of academic articles in the medical field). This database includes duttrabenazine. Austedo is indicated for the treatment of Huntington's disease-related chorea. (Included on the US product label) Austedo is indicated for the treatment of tardive dyskinesia in adults. (Included on the US product label) Deuterated benazine is a vesicular monoamine transporter type 2 (VMAT2) inhibitor that depletes presynaptic dopamine and is used to treat hyperkinesis. This study aimed to explore the safety, tolerability, and preliminary efficacy of deuterated benazine in adolescents with Tourette syndrome (TS) and moderate to severe tic disorders. In this open-label study of TS-related tic disorders in patients aged 12–18 years, the dose of deuterated benazine was gradually increased to 36 mg/day over 6 weeks to adequately suppress tic symptoms without significant adverse events (AEs), followed by maintenance of the optimal dose for 2 weeks. An independent, blinded assessor used the Yale Global Tic Severity Scale (YGTSS), which was the primary efficacy endpoint, to assess the severity of tic disorders. Secondary outcome measures included the clinical overall impression of Tourette syndrome (TS-CGI) and the overall impression of change in Tourette syndrome (TS-PGIC). Twenty-three enrolled patients received deuterated benzodiazepine and underwent at least one post-baseline Yale Tourette Syndrome Severity Scale (YGTSS) assessment. The mean (standard deviation) of the baseline YGTSS total tic severity score (TTS) was 31.6 (7.9), which decreased by 11.6 (8.2) points at week 8, representing a 37.6% reduction in tic severity (p<0.0001). The TS-CGI score improved by 1.2 (0.81) points (p<0.0001), and the TS-PGIC results at week 8 showed that 76% of patients experienced significant or highly significant improvement compared to baseline. The mean (standard deviation) daily dose of deuterated benzodiazepine at week 8 was 32.1 (6.6) mg (range 18–36 mg). One week after discontinuation of deuterated benzonazine, the TTS score increased by 5.6 (8.4) points, confirming the drug's efficacy. No serious or severe adverse events were reported. The results of this 8-week open-label study demonstrate that deuterated benzonazine is safe and effective, and improves tic symptoms in adolescent patients with Tourette syndrome (TS) and severe tic disorders.

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Drug Warning
/Black Box Warning/ Warning: Depression and suicidal tendencies in patients with Huntington's disease. Austedo may increase the risk of depression and suicidal thoughts and behaviors (suicidal tendencies) in patients with Huntington's disease. Anyone considering the use of Austedo must weigh the risks of depression and suicidal tendencies against the clinical need to treat chorea. Closely monitor patients for the development or worsening of depression, suicidal tendencies, or abnormal behavioral changes. Patients, their caregivers, and families should be informed of the risks of depression and suicide and should be instructed to promptly report any worrying behaviors to their attending physician. Extra caution should be exercised in patients with a history of depression, suicide attempts, or suicidal ideation, as these conditions are more common in patients with Huntington's disease. Osterdone is contraindicated in patients with suicidal tendencies and in patients with untreated or inadequately treated depression. Huntington's disease is a progressive disorder characterized by changes in mood, cognition, chorea, rigidity, and functional abilities over time. Vesicular monoamine transporter 2 (VMAT2) inhibitors, including deuterated benzodiazepine, may cause deterioration in mood, cognition, rigidity, and functional abilities. Prescribing physicians should periodically reassess the necessity of deuterated benzodiazepine in patients by evaluating its efficacy for chorea and potential adverse reactions, including sedation/sleepiness, depression and suicidal tendencies, Parkinson's syndrome, akathisia, agitation, and cognitive decline. Distinguishing between adverse reactions and progression of the underlying disease can be difficult; dose reduction or discontinuation may help clinicians differentiate between the two possibilities. In some patients, the underlying chorea itself may improve over time, reducing the need for deuterated benzodiazepine. Deuterated benzonazine may increase the risk of akathisia, agitation, and restlessness in patients with Huntington's disease and tardive dyskinesia. In a 12-week double-blind, placebo-controlled trial in patients with Huntington's disease, 4% of patients in the deuterated benzonazine treatment group reported akathisia, agitation, or restlessness, compared to 2% in the placebo group. In patients with tardive dyskinesia, such events occurred in 2% of patients treated with deuterated benzonazine, compared to 1% in those treated with placebo. Patients treated with deuterated benzonazine should be monitored for signs and symptoms of restlessness, as these may be precursors to akathisia. If akathisia occurs during treatment with deuterated benzonazine, the dose of deuterated benzonazine should be reduced; some patients may need to discontinue treatment. It has been reported that some drugs that reduce dopaminergic transmission can cause a potentially fatal symptom cluster, sometimes referred to as neuroleptic malignant syndrome (NMS). Although NMS has not been observed in patients treated with deuterated bubenazine, it has been observed in patients treated with bubenazine (a closely related VMAT2 inhibitor). Clinicians should be alert to signs and symptoms associated with NMS. Clinical manifestations of neuroleptic malignant syndrome (NMS) include high fever, muscle rigidity, altered mental status, and autonomic dysfunction (irregular pulse or blood pressure, tachycardia, excessive sweating, and arrhythmias). Other signs may include elevated creatine phosphokinase, myoglobinuria, rhabdomyolysis, and acute renal failure. Diagnosis of NMS can be complex; similar signs and symptoms may also be present in other serious medical conditions (e.g., pneumonia, systemic infection) and untreated or poorly treated extrapyramidal disorders. Other important considerations in differential diagnosis include central anticholinergic toxicity, heatstroke, drug fever, and primary central nervous system disorders. /Bubenazine/
For more complete data on drug warnings for deuterated bubenazine (14 in total), please visit the HSDB record page.

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Pharmacodynamics
Clinical trials have shown that deuterated bubenazine effectively improves involuntary motor symptoms in patients with tardive dyskinesia by reducing the mean abnormal involuntary movement scale (AIMS) score. In a randomized, double-blind, placebo-controlled crossover study in healthy male and female subjects, a single dose of 24 mg deuterated bubenazine increased the QTc interval by approximately 4.5 ms. The effects of higher doses of deuterated bubenazine or its metabolites have not been evaluated. Studies have shown that deuterated bubenazine and its metabolites can bind to melanin-containing tissues such as the eyes, skin, and hair of pigmented rats. Radioactivity was still detectable in the eyes and hair 35 days after a single oral dose of radiolabeled deuterated bubenazine.

C19H21D6NO3

323.47

323.237

C, 70.55; H, 10.28; N, 4.33; O, 14.84

1392826-25-3

Tetrabenazine;58-46-8;Tetrabenazine Racemate;718635-93-9;(+)-Tetrabenazine;1026016-83-0;(+)-Tetrabenazine-d6;1977511-05-9

73437646

Light yellow to yellow solid powder

3.176

0

4

4

23

425

2

O=C1[C@H](CC(C)C)CN2CCC3=CC(OC([2H])([2H])[2H])=C(OC([2H])([2H])[2H])C=C3[C@@]2([H])C1

MKJIEFSOBYUXJB-VFJJUKLQSA-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/t14-,16-/m1/s1/i3D3,4D3

rel-(3R,11bR)-3-isobutyl-9,10-bis(methoxy-d3)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one

Deutetrabenazine; Tetrabenazine-d6; SD809; GTPL-8707; SD-809; GTPL8707; SD 809; GTPL 8707; trade name Austedo

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: This product requires protection from light (avoid light exposure) during transportation and storage.

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

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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