In Movement Disorders, Benefits and Risks Depend on Tetrabenazine Isomer

The efficacy of tetrabenazine and valbenazine (Ingrezza) in treating movement disorders like tardive dyskinesia (TD) stems from their ability to inhibit vesicular monoamine transporter-2 (VMAT-2).

This pre-synaptic transport protein regulates the uptake and packaging of monoamine neurotransmitters into synaptic vesicles. Inhibiting this transport protein prevents neurotransmitter uptake into presynaptic vesicles and decreases the availability of dopamine. This decrease combats the dopamine supersensitivity caused by dopamine-receptor antagonists that results in TD.

Tetrabenazine’s activity results not from the racemic form of the drug but from its active metabolites. Once taken, tetrabenazine forms a positive and a negative enantiomer, and carbonyl reductase converts each into an alpha and a beta form. As a result, tetrabenazine has 4 isomeric metabolites of dihydrotetrabenazine (HTBZ).

Each isomer has its own profile of VMAT-2 inhibition and off-target binding. Although VMAT-2 inhibition accounts for its desired effect in controlling movement disorders, off-target binding may account for many of its unwanted side effects.

For example, both positive HTBZ isomers are potent VMAT-2 inhibitors with no or minimal off-target effects. In contrast, both negative HTBZ isomers have low affinity for VMAT-2 and exert off-target effects by inhibiting dopaminergic neurons, which causes parkinsonism, and serotonergic neurons, which causes depression.

Until recently, researchers were able to measure only the total concentrations of alpha isomers and of beta isomers instead of quantifying each of the 4 isomers. Now, Heather Skor (pictured) and colleagues at Neurocrine Biosciences in San Diego, California, have developed a method of using liquid chromatography—tandem mass spectrometry to measure the amount of each of the 4 isomers in samples of blood plasma from patients treated with VMAT-2 inhibitors.

They used this method to compare these amounts in samples from 2 groups of patients, each treated with a different VMAT-2 inhibitor for a different movement disorder. The first group took tetrabenazine once daily for chorea from Huntington’s disease (HD), and the second group took valbenazine once daily for TD.

“Through quantification of the individual HTBZ isomers, this study suggests that the activity of tetrabenazine and the activity of valbenazine arise from different HTBZ isomers,” Skor told MD Magazine.

Just a single isomer, positive alpha HTBZ — the only active metabolite shared by valbenazine and tetrabenazine — was detected after valbenazine administration, Skor noted.

Valbenazine and its 2 major metabolites, positive alpha HTBZ and a mono-oxy metabolite, are all active and bind to VMAT-2 very selectively without much off-target binding at serotonergic or dopaminergic sites, Oliver Freudenreich, MD, co-director of the Schizophrenia Clinical and Research Program at Massachusetts General Hospital in Boston, said.

“However, valbenazine itself binds less potently to VMAT-2 compared to HTBZ and can be considered a pro-drug that needs to be converted to the active drug,” Freudenreich said.

Furthermore, previous investigators believed that positive alpha HTBZ was the main VMAT-2 inhibitor in tetrabenazine. However, the Neurocrine Biosciences study team concluded that positive beta HTBZ was because of its greater abundance than that of positive alpha HTBZ in samples from tetrabenazine-treated patients.

In addition, the study team found that negative alpha HTBZ is also abundant in tetrabenazine. However, they noted that negative alpha HTBZ is much less potent than positive beta HTBZ at inhibiting VMAT-2. Moreover, the affinity of negative alpha HTBZ for other targets in the central nervous system is considerably greater than that of positive beta HTBZ.

This off-target affinity may contribute to unwanted side effects of tetrabenazine, such as depression and parkinsonism, according to the researchers.

“Knowledge of individual isomer exposure, not just pooled isomer exposure, is critical to fully understand the potential benefits and risks of tetrabenazine and its analogs,” Skor said.

The study, “Differences in dihydrotetrabenazine isomer concentrations following administration of tetrabenazine and valbenazine,” appeared in the August 3, 2017, issue of Drugs in R & D.