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Uptake Mechanisms
Published in Stephen W. Carmichael, Susan L. Stoddard, The Adrenal Medulla 1986 - 1988, 2017
Stephen W. Carmichael, Susan L. Stoddard
The hydrophobicity of the tetrabenazine-binding site of the chromaffin vesicle monoamine transporter was demonstrated by Scherman, Gasnier, Jaudon et al. (1988). They tested various drugs of different lipophilicities to see how they would displace tritiated dihydrotetrabenazine. The potency of a compound to displace the dihydrotetrabenazine from its binding site was correlated with its lipophilicity. The data indicated that the binding site is hydrophobic and is in equilibrium with the ligand present in the membrane phase.
Clinical Assessment of Patients with Dementia
Published in Zaven S. Khachaturian, Teresa S. Radebaugh, Alzheimer’s Disease, 2019
Information concerning brain function can be obtained through newer approaches to MR imaging and with pharmacological agents that serve as the source of radiation to produce a brain image. Currently utilized modalities are functional MRI, which currently allows visualization and measurement of cerebral blood flow, and radionuclide imaging with PET and SPECT. Functional imaging provides information that can be extremely helpful in differentiating among certain types of cognitive disorders. Although these studies are not used routinely, they are assuming increasing prominence because of their utility. PET studies of cerebral metabolism with [18F]fluorodeoxyglucose have revealed hypometabolism in a characteristic distribution in Alzheimer’s disease, with involvement predominantly in the posterior temporoparietal regions.51 The pattern of hypometabolism is different in progressive supranuclear palsy than in Alzheimer’s disease, involving in the former disorder chiefly the frontal cortex, basal ganglia, and brainstem, and, in Pick’s disease, affecting principally the anterior portions of the frontal and temporal lobes.51,52 In Huntington’s disease the caudate nucleus and putamen are hypometabolic, and, in multiple system atrophy the cerebral cortex, basal ganglia and cerebellum are involved.52 Regional cerebral blood flow can also be imaged, both with PET (utilizing [015]H20) and SPECT (with 99mTc-HMPAO, 123I-IMP, 123I-HIPDM, or 133Xenon), and the distribution of changes in blood flow closely parallels that seen in studies of cerebral metabolism. Thus, the regions of the brain that are hypometabolic in Alzheimer’s disease, progressive supranuclear palsy, Huntington’s disease, olivopontocerebellar atrophy, and multiple system atrophy are also hypoperfused.51-53 Both SPECT and PET studies of cerebral blood flow have proven helpful in differentiating between Alzheimer’s disease, multiple infarct dementia, and normal aging.51 Currently, a variety of ligands are under development that permit visualization of neurotransmitters and neurotransmitter receptors with PET. Among the substances under development are [18F]fluorodopa and [11C]dihydrotetrabenazine for examination of monoaminergic presynaptic terminals, [11C]raclopride for D2 dopaminergic neurotransmitter receptors, and [11C]flu-mazenil for gamma-aminobutyric type A/benzodiazepine receptors.
VMAT2 Inhibitors for the Treatment of Tardive Dyskinesia
Published in Issues in Mental Health Nursing, 2022
Barbara Warren, Dawn Vanderhoef, Jessica Johnson
Deutetrabenazine, a deuterated molecular form of tetrabenazine, is approved for both chorea in Huntington’s disease and TD (Austedo [Prescribing Information], 2020). Incorporating deuterium in place of specific hydrogen atoms is thought to slow metabolism and prolong half-life compared to tetrabenazine allowing for twice-daily administration with food (Schneider et al., 2020). The pharmacologic activity of deutetrabenazine is thought to be similar to tetrabenazine, in that it is mediated by a blend of four isomeric dihydrotetrabenazine metabolites ([+]-alpha, [−]-alpha, [+]-beta, and [−]-beta) that inhibit VMAT2 and have varying affinities for off-target receptors, including dopamine D1 and D2 receptors and serotonin 5-HT1A, 5-HT2A, and 5-HT7 receptors (Grigoriadis et al., 2017; Stahl, 2018). While circulating levels of the four individual isomers of deutetrabenazine have not been published to date, it is likely that they are similar to those of tetrabenazine, with the most selective and potent isomer ([+]-alpha) present at low levels in plasma (Grigoriadis et al., 2017; Skor et al., 2017; Stahl, 2018).
Clinical development of valbenazine for tics associated with Tourette syndrome
Published in Expert Review of Neurotherapeutics, 2021
Robert H. Farber, Angel Angelov, Kristine Kim, Tara Carmack, Dao Thai-Cuarto, Eiry Roberts
Valbenazine, a VMAT2 inhibitor that is FDA-approved to treat TD in adults, is the valine ester of [+]-α-dihydrotetrabenazine (HTBZ) [27,28]. After oral administration, valbenazine is cleaved by hydrolysis into a valine ester, which improves passive absorption from the intestinal tract, and [+]-α-HTBZ, which is a potent and selective VMAT2 inhibitor and one of the active metabolites of tetrabenazine [28,29]. Unlike valbenazine, tetrabenazine is administered as a racemic mixture of 2 enantiomers and reduced to 4 active stereoisomers: [+]-α-HTBZ, [-]-α-HTBZ, [+]-β-HTBZ, and [-]-β-HTBZ [28,30,31]. Of these, only [+]-α-HTBZ and [+]-β-HTBZ have any appreciable inhibitory effects on VMAT2 (the former having highest selectivity for VMAT2 of the 4 isomers but the lowest plasma concentration after oral administration of tetrabenazine), while [-]-α-HTBZ, [-]-β-HTBZ, and [+]-β-HTBZ have some off-target interactions at dopaminergic, serotonergic, and adrenergic receptor sites [28,31].
Deutetrabenazine for the treatment of Huntington’s chorea
Published in Expert Review of Neurotherapeutics, 2018
Hassaan Bashir, Joseph Jankovic
Deutetrabenazine is a reversible VMAT2 inhibitor thought to cause striatal dopamine reduction by blocking presynaptic uptake of dopamine into synaptic vesicles leading to its depletion from presynaptic stores via monoamine oxidase [8]. Deuteration of TBZ does not change its target pharmacology and, therefore, deutetrabenazine and TBZ have similar specificity for VMAT2. Deutetrabenazine is metabolized by liver carbonyl reductase into two active metabolites, alpha-dihydrotetrabenazine (alpha-HTBZ) and beta-dihydrotetrabenazine (beta-HTBZ), both reversible inhibitors of VMAT2 [28]. These metabolites are in turn metabolized by CYP2D6-mediated O-demethylation [29]. Excretion is primarily through urine. Biotransformation is extensive, such that after an oral dose of 25 mg, plasma concentrations of deutetrabenazine are generally below detection levels [28]. Figure 2 shows the metabolism pathway of deutetrabenazine.