58-46-8 Usage
Indications
Tetrabenazine is used for the treatment of hyperkinetic movement disorders like chorea in Huntington's disease, hemiballismus, senile chorea, Tourette syndrome and other tic disorders, and tardive dyskinesia (TD).
Pharmacokinetics
A thorough review of the medical literature reveals a paucity of information regarding the pharmacodynamics of TBZ. After intravenous administration of radiolabeled 3H-TBZ, 54% was excreted in urine after 48h[16]. A 1987 study found no evidence of unchanged TBZ in the urine of four patients indicating extensive metabolism[17]. TBZ is excreted in human breast milk, thus breastfeeding while taking TBZ should be avoided. Although no case of teratogenicity has been reported, TBZ does cross the placenta[18].
After oral administration, TBZ is rapidly absorbed within 1 hour; however, the systemic bioavailability of the parent drug is low(5%) due to a high first-pass metabolism[19]. TBZ undergoes first-pass metabolism, by hepatic carbonyl reductase, to at least two isomers of dihydrotetrabenazine (DHTBZ): alpha-DHTBZ and beta-DHTBZ[20]. Both metabolites are pharmacologically active, with alpha-DHTBZ demonstrating activity similar to the parent drug[6]. Both metabolites reach Cmax within 1 to 2 hours and are primarily metabolized by cytochrome P450(CYP) 2D6(CYP2D6). The t1?2 of alphaand beta-DHTBZ ranges from 2 to 8 hours and 2 to 5 hours, respectively[6, 7].
In humans, the steady-state AUC values of the DHTBZ metabolites are 82.6 to 199 fold higher than that of TBZ[21]. In rats; the mean (SD) Vd of DHTBZ is 7.8 (4.08) L/kg. Protein binding of TBZ, alpha-DHTZ, and beta-DHTBZ ranges from 82% to 85%, 60% to 68%, and 59% to 63%, respectively[6].
Neither TBZ nor its metabolites induce or inhibit major CYP450 isozymes. Therefore, TBZ will not interfere with metabolism of other drugs that are CYP450 substrates. However, because some of the DHTBZ metabolites are substrates for CYP2D6, other drugs that induce or inhibit this isozyme may alter DHTBZ concentrations[6, 7].
Mode of action
In the CNS, neurons communicate with one another through the release of neurotransmitters. Neurotransmitters are synthesized in the neuronal cytoplasm and then packaged into vesicles; otherwise, they undergo rapid degradation by ubiquitous monoamine oxidases. TBZ acts as a reversible inhibitor of monoamine uptake into granular vesicles of presynaptic neurons[22,23] through its ability to bind to vesicular monoamine transporter (VMAT)-2[24] thereby potentiating monoamine degradation in the cytoplasm. Monoamine neurotransmitters that are depleted via VMAT2 inhibition by TBZ include serotonin, dopamine, and norepinephine[23, 25]. In one in vivo study of rats, TBZ decreased dopamine levels by 40%, serotonin by 44% and norepinephrine by 41% in the brain[26]. Levels of acetylcholine, aspartate and glutamate were decreased to a lesser degree. In an autopsy study of 18 patients with Huntington’s disease(HD), those who had received TBZ displayed an overall depletion of monoamines in the caudate, amygdala, hip-pocampus and temporal lobe when compared with patients not exposed to TBZ[27,28]. The most pronounced depletion involved dopamine in the caudate nucleus.
VMAT2, a large protein with 12 transmembrane helices encoded by the VMAT2 gene and localized to chromosome 10q25, is expressed mostly in the brain. In contrast, VMAT1, encoded by a gene on chromosome 8p21.3, is expressed in the periphery[29]. TBZ binds with high affinity to VMAT2, but not to VMAT1[30].
Although in vitro studies have shown that TBZ blocks dopamine D2 receptors, as suggested by its ability to inhibit(3H) spiperone binding to striatal membranes with a Ki of approximately 2.1 × 10-6M, this affinity is 1000-fold lower than its affinity for VMAT2[31,32]. Therefore, it is unlikely that the weak D2 receptor antagonism is responsible for TBZ clinical effects, although it may be possibly involved in acute dystonic reactions rarely reported with TBZ[33]. Although TBZ has also been found to block the pharmacologic action of apomorphine, a dopamine agonist[23], providing further evidence of dopamine receptor-blocking activity, this action of TBZ is relatively weak and most likely explains the low risk of TBZ-induced TD. The presynaptic depletion and weak postsynaptic dopamine receptor inhibition may be responsible for increased dopamine turnover as suggested by the increased levels of the major dopamine metabolite, homovanillic acid, in the cerebrospinal fluid of patients with HD taking TBZ[7].
Safety & Tolerability
TBZ has been used most commonly in the range of 25 200mg/day, although a typical therapeutic dose is 50 75 mg/day. In studies and in daily practice, TBZ is slowly titrated from approximately 25 mg/day in two or three divided doses up to 150mg/day in increments of 25 mg/week. Given the short half-life, dosing three-times per day is sometimes necessary. The dose escalation is stopped when the patient experiences intolerable side effects or a satisfactory effect. Nearly all drug-related side effects can be eradicated by lowering the dose. Therefore, most studies with TBZ are designed to increase the dose until intolerable side effects are noted and then the dose is slightly decreased to alleviate the side effects. Using this technique of dose escalation, it is not surprising that many patients develop side effects. The dose-dependent nature of side effects is an important point to consider when discussing the adverse event profile of TBZ[18,34,35]. Common side effects include sedation, parkinsonism, depression, insomnia, and akathisia, all of which are reversible[16]. Several investigators have observed that younger patients tolerate TBZ better than the elderly. These findings have been confirmed and reported that younger patients (<50 years) experienced more insomnia and depression, while older patients were more likely to develop parkinsonism[37]. Serious side effects of TBZ described in the literature include severe hyperthermia, neuroleptic malignant syndrome (NMS), acute dystonic reaction[33], pneumonia, severe dysphagia[1,10] and suicide[6]. NMS usually occurs within the first 4 weeks of treatment, but may be delayed several years[38,39]. Prescribing physicians should be aware that a number of publications mention fatalities occurring in those taking TBZ without an obvious etiology. It should be considered that the frequency of dysphagia, suicide and death would be expected to be increased in a study population of patients with HD. Most authors state that the deaths were not directly related to TBZ, but the frequency of unexplained death in certain clinical studies warrants caution and close monitoring of patients' physical and mental well-being throughout the course of treatment.
Precautions
When you take tetrabenazine, you should follow the following tips[40]:
Tell all of your health care providers that you take tetrabenazine including your doctors, nurses, pharmacists, and dentists.
You should avoid driving and doing other tasks or actions that call for you to be alert until you see how tetrabenazine affects you.
To lower the chance of feeling dizzy or passing out, you should rise slowly if you have been sitting or lying down. Be careful when you go up and down stairs.
You should often have your blood pressure checked and keep in touch with your doctor. Talk with your doctor before you drink alcohol or use other drugs and natural products that slow your actions. If you have Huntington's disease, your signs can still get worse while you use drugs like this one. Call your doctor right away if you have any signs that are new or worse. Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using tetrabenazine while you are pregnant. Tell your doctor if you are breast-feeding. You will need to talk about any risks to your baby.
Reference
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HuysD,Hardenacke K,PoppeP,etal.Update on the role of antipsychotics in the treatment of Tourette syndrome. Neuropsychiatr Dis Treat. 2012;8:95–104.
Fasano A, Bentivoglio AR. Tetrabenazine. Expert Opin Pharmacother. 2009;10:2883–2896.
ScottLJ.Tetrabenazine:for chorea associated with Huntington’s disease. CNS Drugs. 2011;25:1073–1078.
JankovicJ,Clarence-SmithK.Tetrabenazine for the treatment of chorea and other hyperkinetic movement disorders. Expert Rev Neurother. 2011;11:1509 –1523.
de Tommaso M, Serpino C, Sciruicchio V. Management of Huntington’s disease: role of tetrabenazine. Ther Clin Risk Manag. 2011;7:123–129.
Frank S. Tetrabenazine: the first approved drug for the treatment of chorea in US patients with Huntington disease. Neuropsychiatr Dis Treat. 2010;6:657– 665.
Poon LH, Kang GA, Lee AJ. Role of tetrabenazine for Huntington’s disease-associated chorea. Ann Pharmacother. 2010;44:1080 –1089.
Leung JG, Breden EL. Tetrabenazine for the treatment of tardive dyskinesia. Ann Pharmacother. 2011;45:525–531.
Guay DR. Tetrabenazine, a monoamine-depleting drug used in the treatment of hyperkinetic movement disorders. Am J Geriatr Pharmacother. 2010;8:331–373.
Quinn GP, Shore PA, Brodie BB. Biochemical and pharmacological studies of RO 19569 (tetrabenazine), a nonindole tranquilizing agent with reserpine-like effects. J. Pharmacol. Exp. Ther. 127, 103–109 (1959).
Scherman D, Henry JP. Acido–basic properties of the catecholamine uptake inhibitors tetrabenazine and dihydrotetrabenazine. Biochimie 64, 915–921 (1982).
Roberts MS, Watson HM, McLean S, Millingen KS. Determination of therapeutic plasma concentrations of tetrabenazine and an active metabolite by high-performance liquid chromatography. J. Chromatogr. 226, 175–182 (1981).
Stumpf W. Untersuchungen uber ‘Nitoman’. Psychiatr. Neurol. 140, 63–68 (1960).
Mehvar R, Jamali F, Watson MW, Skelton D. Pharmacokinetics of tetrabenazine and its major metabolite in man and rat. Bioavailability and dose dependency studies. Drug. Metab. Dispos. 15, 250–255 (1987).
Roberts MS, McLean S, Millingen KS, Galloway HM. The pharmacokinetics of tetrabenazine and its hydroxy metabolite in patients treated for involuntary movement disorders. Eur. J. Clin. Pharmacol. 29, 703–708 (1986).
RobertsMS,McLeanS,MillingenKS,GallowayHM.The pharmacokinetics of tetrabenazine and its hydroxy metabolite in patients treated for involuntary movement disorders. Eur J Clin Pharmacol. 1986;29:703–708.
YaoZ,WeiX,WuX,etal.Preparationandevaluationof tetrabenazine enantiomers and all eight stereoisomers of dihydrotetrabenazine as VMAT2 inhibitors. Eur J Med Chem. 2011;46:1841–1848.
Mehvar R, Jamali F, Watson MW, et al. Pharmacokinetics of tetrabenazine and its major metabolite in man and rat. Bioavailability and dose dependency studies. Drug Metab Dispos. 1987;15:250 –255.
Caine ED, Shoulson I. Psychiatric syndromes in Huntington’s disease. Am J Psychiatry. 1983;140:728 –733.
Lawrence AD, Sahakian BJ, Hodges JR, et al. Executive and mnemonic functions in early Huntington’s disease. Brain. 1996;119(Pt 5):1633– 1645.
Kirkwood SC, Su JL, Conneally P, et al. Progression of symptoms in the early and middle stages of Huntington disease. Arch Neurol. 2001;58:273–278.
Ho AK, Sahakian BJ, Brown RG, et al. Profile of cognitive progression in early Huntington’s disease. Neurology. 2003;61:1702–1706.
Lanska DJ, Lanska MJ, Lavine L, et al. Conditions associated with Huntington’s disease at death. A casecontrol study. Arch Neurol. 1988;45: 878 – 880.
Sorensen SA, Fenger K. Causes of death in patients with Huntington’s disease and in unaffected first degree relatives. J Med Genet. 1992;29: 911–914. Huntington’sDiseaseCollaborative Research
Group. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell. 1993;72:971–983.
RubinszteinDC,LeggoJ,ColesR,et al. Phenotypic characterization of individuals with 30-40 CAG repeats in the Huntington disease (HD) gene reveals HD cases with 36 repeats and apparently normal elderly individuals with 36-39 repeats. Am J Hum Genet. 1996;59:16 –22.
Ranen NG, Stine OC, Abbott MH, et al. Anticipation and instability of IT-15 (CAG)n repeats in parentoffspring pairs with Huntington disease. Am J Hum Genet. 1995;57:593– 602.
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https://www.drugs.com/cdi/tetrabenazine.html
Originator
Nitoman,Roche,UK,1960
Manufacturing Process
280 grams of 1-carbethoxymethyl-6,7-dimethoxy-1,2,3,4-
tetrahydroisoquinoline, 150 grams of mono-isobutylmalonic acid dimethyl
ester and 35 grams of paraformaldehyde were refluxed for 24 hours in 1,000
ml of methanol. Upon cooling, 1-carbethoxymethyl-2-(2,2-dicarbomethoxy-4-
methyl-n-pentyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline crystallized;
MP after recrystallization from methanol, 94° to 96°C. The latter was
subjected to Dieckmann cyclization, hydrolysis and decarboxylation in the
following manner.28 grams of sodium was dissolved in 650 ml of absolute ethanol, the solution
was concentrated to dryness, and the residue was mixed with 3,600 ml of
toluene and 451 grams of the intermediate prepared above. The mixture was
heated, and the methanol formed by condensation was distilled off until the
boiling point of toluene was reached. The mixture was thereupon refluxed for
2 hours, and then it was concentrated to dryness. The residue was dissolved
in 5,200 ml of 3 N hydrochloric acid and heated for 14 hours at 120°C,
thereby effecting hydrolysis and decarboxylation. The mixture was cooled,
washed with diethyl ether, decolorized with carbon, made alkaline and taken
up in diethyl ether. The process yields 2-oxo-3-isobutyl-9,10-dimethoxy-
1,2,3,4,6,7-hexahydro-11b-benzo[a]quinolizine; MP after recrystallization from
diisopropyl ether, 126° to 128°C.
Therapeutic Function
Tranquilizer
Biological Activity
Potent inhibitor of vesicular monoamine uptake; depletes stores of dopamine, serotonin and noradrenalin. Binds with high affinity (IC 50 = 3.2 nM) to vesicular monoamine transporter (VMAT) in chromaffin granule membranes and displays higher affinity for VMAT2 than VMAT1. Also reported to block dopamine receptors. Causes behavioral depression; inhibits locomotor activity and produces hypothermia upon systemic administration in rats and mice.
Biochem/physiol Actions
Primary TargetVMAT2
Purification Methods
Crystallise it from MeOH. The hydrochloride has m 208-210o, and the oxime has m 158o (from EtOH). [Beilstein 21 III/IV 6488.]
References
1) Scherman?et al. (1983),?Characterization of the monoamine carrier of chromaffin granule membrane by binding of [2-3H]dihydrotetrabenazine; Proc. Natl. Acad. Sci. USA,?80?584
2) Peter?et al. (1996),?Chimeric vesicular monoamine transporters identify structural domains that influence substrate affinity and sensitivity to tetrabenazine; J. Biol. Chem.,?271?2979
3) Schafer?et al. (2013),?Localization and expression of VMAT2 across mammalian species: a translational guide for it’s visualization and targeting in health and disease; Adv. Pharmacol.,?68?319
4) Sakano?et al. (2014),?VMAT2 identified as a regulator of late-stage β-cell differentiation; Nat. Chem. Biol.,?10?141
Check Digit Verification of cas no
The CAS Registry Mumber 58-46-8 includes 5 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 2 digits, 5 and 8 respectively; the second part has 2 digits, 4 and 6 respectively.
Calculate Digit Verification of CAS Registry Number 58-46:
(4*5)+(3*8)+(2*4)+(1*6)=58
58 % 10 = 8
So 58-46-8 is a valid CAS Registry Number.
InChI:InChI=1/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
58-46-8Relevant articles and documents
Real-Time Monitoring of Solid-Liquid Slurries: Optimized Synthesis of Tetrabenazine
Sato, Yusuke,Liu, Junliang,Kukor, Andrew J.,Culhane, Jeffrey C.,Tucker, John L.,Kucera, David J.,Cochran, Brian M.,Hein, Jason E.
, p. 14069 - 14078 (2021/07/26)
Solid-liquid slurries are vital and increasingly prevalent in the pharmaceutical and chemical industries. Despite the importance of these heterogeneous systems, process control and optimization are fundamentally hindered by a lack of compatible real-time analytical techniques. We present herein an online HPLC monitoring platform enabling access to real-time compositional information on slurries. We demonstrate the system by investigating the heterogeneous synthesis reaction of tetrabenazine. Furthermore, we integrated our online HPLC platform with the orthogonal monitoring techniques of a pH probe and a microscopic imaging probe to provide additional mechanistic insight. These combined insights enable the optimization of tetrabenazine synthesis in terms of reaction time, byproduct formation, and diastereomeric purity of the final product.
Rapid construction of tetrahydropyridine scaffolds via formal imino Diels-Alder reactions of Schiff bases and Nazarov reagents
Wu, Yen-Ku,Rawal, Viresh H.
, p. 8827 - 8831 (2019/10/22)
Described is a one-flask, two-step method for the synthesis of highly functionalized piperidines. The process involves formal [4 + 2] cycloadditions of Schiff bases and Nazarov reagents, followed by facile elaborations of the initial cycloadducts. Notably, these aza-annulations are facilitated by protic solvents and proceed smoothly under ambient conditions, without other additives. The synthetic utility of this annulation protocol is further showcased through a concise, convergent synthesis of (±)-tetrabenazine.
Novel Process for Preparation of Tetrabenazine and Deutetrabenazine
Ray, Purna Chandra,Pawar, Yogesh Dadaji,Singare, Dnyaneshwar Tukaram,Deshpande, Tushar Nandkumar,Singh, Girij Pal
, p. 520 - 526 (2018/04/27)
A novel process for the synthesis of tetrabenazine (1) and deutetrabenazine (2), two well-known drugs used for the treatment of chorea associated with Huntington's disease, has been developed. All of the reaction parameters were optimized through a series of reactions and by using Design of Experiment techniques. The newly developed methods are industrially scalable and employ cheap, commercially available raw materials and hence are highly efficient. The added advantage is that the developed processes evade the use of genotoxic alkylating agents and therefore could be considered as safe and viable alternatives to the existing methods.
Redox-Annulation of Cyclic Amines and β-Ketoaldehydes
Chen, Weijie,Seidel, Daniel
, p. 1024 - 1027 (2016/03/15)
Benzo[a]quinolizine-2-one derivatives are readily assembled from 1,2,3,4-tetrahydroisoquinoline and β-ketoaldehydes by means of a new intramolecular redox-Mannich process. These reactions are promoted by simple acetic acid and are thought to involve azomethine ylides as reactive intermediates.
A concise synthesis of tetrabenazine: An intramolecular aza-prins-type cyclization via oxidative c-h activation
Son, Young Wook,Kwon, Tae Hui,Lee, Jae Kyun,Pae, Ae Nim,Lee, Jae Yeol,Cho, Yong Seo,Min, Sun-Joon
, p. 6500 - 6503 (2012/02/02)
A concise synthesis of tetrabenazine and dihydrotetrabenazine is described. The key feature of this synthesis is the intramolecular aza-Prins-type cyclization of an amino allylsilane via oxidative C-H activation. 2011 American Chemical Society.
SUBSTITUTED 3-ISOBUTYL-9, 10-DIMETHOXY-1,3,4,6,7,11B-HEXAHYDRO-2H-PYRIDO[2,1-A] ISOQUINOLIN-2-OL COMPOUNDS AND METHODS RELATING THERETO
-
Page/Page column 13-14, (2008/12/05)
Substituted 3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol compounds are disclosed that are inhibitors of the vesicular monoamine transporter 2 (VMAT2). The compounds of this invention have the structure (I): wherein R1 is as defined herein, including stereoisomers and pharmaceutically acceptable salts and solvates thereof. Also disclosed are compositions containing a compound of this invention in combination with a pharmaceutically acceptable carrier, as well as methods relating to the use in a subject in need thereof.
