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Tetrabenazine | CAS No: 58-46-8 | GMP-certified suppliers
A medication that treats hyperkinetic movement disorders including chorea in Huntington’s disease, Tourette syndrome, and tardive dyskinesia by modulating central nervous system activity.
Therapeutic categories
Primary indications
- Treatment of hyperkinetic movement disorders like chorea in Huntington's disease, hemiballismus, senile chorea, Tourette syndrome and other tic disorders, and tardive dyskinesia
Product Snapshot
- Tetrabenazine is an oral small molecule formulation available in multiple tablet and coated tablet forms
- It is indicated for the treatment of hyperkinetic movement disorders including chorea associated with Huntington's disease, hemiballismus, senile chorea, Tourette syndrome, other tic disorders, and tardive dyskinesia
- Tetrabenazine is approved in the US and Canada and also holds investigational status in certain markets
Clinical Overview
Pharmacologically, tetrabenazine is classified as a tetrahydroisoquinoline derivative. Its mechanism of action centers on reversible inhibition of the human vesicular monoamine transporter type 2 (VMAT2) with a Ki of approximately 100 nM. This inhibition reduces the uptake of monoamine neurotransmitters—dopamine, serotonin, and norepinephrine—into synaptic vesicles, leading to their depletion within presynaptic neurons, particularly in basal ganglia regions. Decreased dopamine availability underpins its efficacy in reducing hyperkinetic movements due to dopamine’s essential role in motor control. Tetrabenazine has weak affinity for dopamine D2 receptors (Ki ~2100 nM), indicating minimal direct dopaminergic receptor interaction.
Pharmacokinetic data indicate prolonged retention of the drug or its metabolites in melanin-containing tissues, including eyes and skin, with radioactivity detectable up to 21 days post-dose in animal models. Dose-dependent prolongation of the QTc interval has been observed clinically at doses around 50 mg, categorizing tetrabenazine among agents with highest risk for QTc prolongation. It is a substrate of cytochrome P450 CYP2D6, requiring consideration of metabolic interactions and patient variability in CYP2D6 activity.
Safety considerations include monitoring for QTc interval changes, potential neuropsychiatric side effects, and cautious use in populations with underlying cardiac conditions. Tetrabenazine’s pharmacological profile necessitates comprehensive evaluation of drug-drug interactions, especially with other CYP2D6 substrates or QTc-prolonging agents.
From a sourcing perspective, high-purity API material should comply with regulatory standards for quality and reproducibility. Given its metabolic liabilities and safety profile, consistent batch-to-batch quality control and thorough impurity characterization are essential to maintain clinical safety and efficacy outcomes.
Identification & chemistry
| Generic name | Tetrabenazine |
|---|---|
| Molecule type | Small molecule |
| CAS | 58-46-8 |
| UNII | Z9O08YRN8O |
| DrugBank ID | DB04844 |
Pharmacology
| Summary | Tetrabenazine is a reversible inhibitor of the vesicular monoamine transporter type 2 (VMAT2) that reduces the storage and release of monoamine neurotransmitters, including dopamine, serotonin, and norepinephrine, within basal ganglia neurons. By depleting synaptic dopamine, it modulates hyperkinetic movement disorders such as chorea and tics. Additionally, tetrabenazine exhibits weak affinity for dopamine D2 receptors and has been associated with QTc interval prolongation at higher doses. |
|---|---|
| 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). |
| Pharmacodynamics | Prolongation of the QTc interval has been observed at doses of 50 mg. In rats, it has been observed that tetrabenazine or its metabolites bind to melanin-containing tissues such as the eyes and skin. After a single oral dose of radiolabeled tetrabenazine, radioactivity was still detected in eye and fur at 21 days post dosing. |
Targets
| Target | Organism | Actions |
|---|---|---|
| Synaptic vesicular amine transporter | Humans | inhibitor |
| Dopamine D2 receptor | Humans | inhibitor |
ADME / PK
| Absorption | 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 |
|---|---|
| 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. |
| Protein binding | Tetrabenazine = 82 - 88%; α-HTBZ = 60 - 68%; β-HTBZ = 59 - 63%. |
| Metabolism | 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. |
| Route of elimination | 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. |
| Volume of distribution | 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. |
| Clearance | IV, 1.67 L/min in HD or tardive dyskinesia patients |
Formulation & handling
- Tetrabenazine is a small molecule API formulated exclusively for oral administration as tablets.
- It has moderate lipophilicity (LogP 3.4) and low water solubility, which may impact dissolution and bioavailability considerations.
- Alcohol should be avoided during administration due to enhanced CNS depressant effects; food intake does not significantly affect absorption.
Regulatory status
| Lifecycle | The API's patent protection has expired in both Canada and the US, allowing for generic entry and increased market competition. As a result, the product is in a mature market phase with established regulatory approvals across both regions. |
|---|
| Markets | Canada, US |
|---|
Supply Chain
| Supply chain summary | The manufacturing and supply landscape for Tetrabenazine involves multiple originator companies engaged primarily in packaging and distribution within North American markets, including Canada and the US. Branded products are present in these regions, with various formulations available under distinct brand names. Patent expiry status indicates that generic competition may already be established or emerging in these markets. |
|---|
Safety
| Toxicity | Dose-limiting adverse effects are sedation, parkinsonism, akathsia, and depression. LD50 oral, mouse: 550 mg/kg |
|---|
- Dose-limiting adverse effects include sedation, parkinsonism, akathisia, and depression
- Oral LD50 in mice is 550 mg/kg, indicating moderate acute toxicity
- Handle with precautions to minimize exposure due to central nervous system-related toxicity risks
Tetrabenazine is a type of Other central nervous system agents
Others
Tetrabenazine (Other central nervous system agents), classified under Central Nervous System Agents
Central Nervous System (CNS) Agents are a crucial category of pharmaceutical Active Pharmaceutical Ingredients (APIs) that specifically target the central nervous system. The CNS encompasses the brain and spinal cord, playing a vital role in regulating and controlling various bodily functions, including cognition, movement, emotions, and sensory perception. These agents are designed to interact with specific receptors, enzymes, or ion channels within the CNS to modulate neural activity and restore normal functioning.
CNS agents comprise a diverse range of pharmaceutical APIs, including analgesics, anesthetics, antipsychotics, sedatives, hypnotics, anti-epileptics, and antidepressants. Each subcategory addresses distinct neurological disorders and conditions. For instance, analgesics alleviate pain by targeting receptors in the brain and spinal cord, while antipsychotics are employed to manage psychosis symptoms in mental illnesses such as schizophrenia.
The development of CNS agents involves rigorous research, molecular modeling, and extensive clinical trials to ensure safety, efficacy, and specific target engagement. Pharmaceutical companies invest significant resources in identifying novel drug targets, synthesizing new compounds, and optimizing their pharmacological properties. These agents undergo rigorous regulatory evaluations and must adhere to stringent quality standards and guidelines.
Given the prevalence of CNS disorders globally, the market demand for effective CNS agents is substantial. The development of innovative CNS APIs not only improves patient outcomes but also provides valuable commercial opportunities for pharmaceutical companies. Continued advancements in CNS agent research and development hold the promise of groundbreaking therapies that can improve the quality of life for individuals affected by neurological conditions.
Tetrabenazine API manufacturers & distributors
Compare qualified Tetrabenazine API suppliers worldwide. We currently have 9 companies offering Tetrabenazine API, with manufacturing taking place in 3 different countries. Use the table below to review supplier type, countries of origin, certifications, product portfolio and GMP audit availability.
| Supplier | Type | Country | Product origin | Certifications | Portfolio |
|---|---|---|---|---|---|
| Centaur Pharma | Producer | India | India | CoA, GMP, USDMF, WC | 40 products |
| Corden Pharma | Producer | Germany | France | CoA, GMP, USDMF | 45 products |
| Enaltec Labs | Producer | India | India | CoA, WC | 16 products |
| Hetero Drugs | Producer | India | India | CoA, GMP, USDMF, WC | 98 products |
| Mylan | Producer | India | India | CoA, GMP, USDMF, WC | 201 products |
| Piramal Pharma Solutions | Producer | India | India | CoA, USDMF, WC | 44 products |
| Rolabo Outsourcing | Producer | Spain | Spain | CoA, USDMF | 11 products |
| Sun Pharma | Producer | India | India | CoA, GMP, USDMF, WC | 219 products |
| Synkem | Producer | France | France | CoA, JDMF | 4 products |
When sending a request, specify which Tetrabenazine API quality you need: for example EP (Ph. Eur.), USP, JP, BP, or another pharmacopoeial standard, as well as the required grade (base, salt, micronised, specific purity, etc.).
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