Differences in Dihydrotetrabenazine Isomer Concentrations Following Administration of Tetrabenazine and Valbenazine
| Autor: | Haig Bozigian, Gordon Loewen, Evan Smith, Dimitri E. Grigoriadis, Christopher F. O'Brien, Heather Skor |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Adult Male Stereochemistry Metabolite Tetrabenazine Pharmacology Tardive dyskinesia Dihydrotetrabenazine 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Isomerism Tandem Mass Spectrometry medicine Potency Humans Tardive Dyskinesia Valbenazine Original Research Article Active metabolite Adrenergic Uptake Inhibitors Biological activity Valine Middle Aged medicine.disease 030104 developmental biology Huntington Disease chemistry Female 030217 neurology & neurosurgery medicine.drug Chromatography Liquid |
| Zdroj: | Drugs in R&D |
| ISSN: | 1179-6901 1174-5886 |
| Popis: | Background Tetrabenazine (TBZ) activity is thought to result from four isomeric dihydrotetrabenazine (HTBZ) metabolites ([+]-α-HTBZ, [−]-α-HTBZ, [+]-β-HTBZ, [−]-β-HTBZ). Each isomer has a unique profile of vesicular monoamine transporter 2 (VMAT2) inhibition and off-target binding. Previously published data only report total isomer (α) and (β) concentrations. We developed a method to quantify the individual HTBZ isomers in samples from patients with Huntington’s disease receiving TBZ. For comparison, concentrations of [+]-α-HTBZ, the single active metabolite shared by valbenazine (VBZ) and TBZ, were determined in samples from patients with tardive dyskinesia receiving VBZ. Methods A liquid chromatography–tandem mass spectrometry (LC-MS/MS) method was developed and validated for quantitation of the four individual HTBZ isomers. Concentrations were determined in serum from patients with Huntington’s disease administered TBZ and plasma from patients with tardive dyskinesia administered VBZ once daily. Results In patients administered TBZ, [−]-α-HTBZ and [+]-β-HTBZ were the most abundant HTBZ isomers while [−]-β-HTBZ and [+]-α-HTBZ were present as minor metabolites. Only [+]-α-HTBZ was observed in patients administered VBZ. Conclusions Based on relative abundance and potency, [+]-β-HTBZ appears to be the primary contributor to VMAT2 inhibition by TBZ, a finding in contrast with the generally held assertion that [+]-α-HTBZ is the major contributor. [−]-α-HTBZ, the other abundant TBZ metabolite, has much lower VMAT2 inhibitory potency than [+]-β-HTBZ, but increased affinity for other CNS targets, which may contribute to off-target effects of TBZ. In contrast, pharmacological activity for VBZ is derived primarily from [+]-α-HTBZ. Individual HTBZ isomer concentrations provide a more clinically relevant endpoint for assessing on- and off-target effects of TBZ than total isomer concentrations. |
| Databáze: | OpenAIRE |
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