Liquid chromatography–tandem mass spectrometric assay for the determination of tetrabenazine and its active metabolites in human plasma: a pharmacokinetic study

Abstract

A simple, rapid and sensitive liquid chromatography-tandem mass spectrometric (LC-MS/MS) assay method has been developed and fully validated for the simultaneous quantification of tetrabenazine and its active metabolites α-dihydrotetrabenazine and β-dihydrotetrabenazine in human plasma. Tetrabenazine d7 was used as internal standard (IS). The analytes were extracted from 200 μL aliquots of human plasma via solid-phase extraction using C18 solid-phase extraction cartridges. The reconstituted samples were chromatographed on a Zorbax SB C18 column using a 60:40 (v/v) mixture of acetonitrile and 5 mm ammonium acetate as the mobile phase at a flow rate of 0.8 mL/min. The API-4000 LC-MS/MS in multiple reaction-monitoring mode was used for detection. The calibration curves obtained were linear (r(2) ≥ 0.99) over the concentration range of 0.01-5.03 ng/mL for tetrabenazine and 0.50-100 ng/mL for α-dihydrotetrabenazine and β-dihydrotetrabenazine. Method validation was performed as per Food and Drug Administration guidelines and the results met the acceptance criteria. The method is precise and sensitive enough for its intended purpose. A run time of 2.5 min for each sample made it possible to analyze more than 300 plasma samples per day. The proposed method was found to be applicable to clinical studies.

Development and validation of a UPLC‐MS/MS method for the determination of cucurbitacin B in rat plasma and application to a pharmacokinetic study

“…It was required that greater than two‐thirds of reanalyzed samples had a relative difference in concentration of within 20% of the original assay (Derangula et al ., ).…”

Treatment of myoclonus-dystonia syndrome with tetrabenazine

“…VMAT2 is also inhibited by the two major metabolites of tetrabenazine, α-dihyrotetrabenazine and β-dihydrotetrabenazine. Recent pharmacokinetic analyses of six healthy controls found that the time to attainment of maximum plasma concentration ( t max ) for tetrabenazine, α-dihyrotetrabenazine, and β-dihydrotetrabenazine was approximately 1 hr [8]. The terminal half-lives ( t 1/2 ) for tetrabenazine, α-dihyrotetrabenazine and β-dihydrotetrabenazine were 2.1, 7.6 and 5.9 hrs, respectively.…”

Comparing pharmacologic mechanism of action for the vesicular monoamine transporter 2 (VMAT2) inhibitors valbenazine and deutetrabenazine in treating tardive dyskinesia: does one have advantages over the other?

“…Active isomers of 2 unrelated doses of valbenazine and deutetrabenazine within their therapeutic dosing ranges were determined at maximum plasma drug level (Cmax) following administration in separate studies. [16][17][18][19][20] Valbenazine has only 1 active isomer, and deutetrabenazine has 4, with the (-) alpha and the ( + ) beta isomers present in sufficient amounts to exert pharmacologic activity. Active isomers of deutetrabenazine and valbenazine cannot be directly compared.…”