Tetrabenazine Other names: Tetrabenzaine

Tetrabenazine is a synthetic derivative of benzylquinolizine that causes depletion of dopamine and other monoamines in the central nervous system.

The precise mechanism by which tetrabenazine exerts its effects is unknown, but is believed to be related to its effect as a reversible depletor of monoamines (such as dopamine, serotonin, norepinephrine, and histamine) from nerve terminals.

Studies conducted in vitro and in vivo have shown that tetrabenazine is a selective inhibitor of monoamine transportation into pre-synaptic neuronal vesicles, by reversible inhibition of the VMAT2 (vesicular monamine transporter 2), which is principally located in the central nervous system. Studies have shown that α-dihydrotetrabenazine, one of the principal metabolite of tetrabenazine, has a similar affinity and more significant selectivity for VMAT2.

At a synaptic level tetrabenazine and α-dihydrotetrabenazine creates a reversible depletion of monamines in the presynaptic terminals. Within the CNS tetrabenazine and α-dihydrotetrabenazine causes preferential depletion of dopamine from nerve terminals. Neurotransmitter depletion by a single dose of tetrabenazine is reversible and lasts only a few hours.

Absorption/Distribution

Tetrabenazine is quickly and completely absorbed after oral administration. Its absorption is not affected by the intake of food.

Clinical testing has shown that a single dose of tetrabenazine undergoes extensive absorption (≥75%) from the gastro-intestinal tract.

Plasma levels of tetrabenazine decline rapidly, with a half-life of 1.9 hours.

Biotransformation

Tetrabenazine has a low and erratic bioavailability (4.9% to 6%). It appears to be extensively metabolised by first-pass metabolism. Major metabolites, alpha-dihydrotetrabenazine (α-HTBZ) and β-dihydrotetrabenazine (ß-HTBZ) are formed by reduction.

Primary metabolites α-HTBZ and ß-HTBZ are mainly metabolised by cytochrome P450 2D6 liver enzyme. CYP2D6 inhibitors may increase the plasma concentration of these metabolites.

Elimination

Tetrabenazine is mostly eliminated in metabolised form in urine (only 2.1% of tetrabenazine is excreted unchanged in the urine).

Linearity

After administration of single doses from 12.5 to 50 mg mg of tetrabenazine, the maximum plasma concentration and the area under the curve increased in proportion to the dose, indicating a linear kinetic.

Special populations

Hepatic impairment

Mild and moderate hepatic impairment increases the exposure and prolongs the half-lives of tetrabenazine and hydroxytetrabenazine (data in 4 patients with Child Pugh score 5-6 and 1 patient with Child Pugh score 9). Severe hepatic impairment has not been studied.

In repeated dose toxicity studies most effects observed are related to the phamacodynamic action of tetrabenazine and reflect central monoamine depletion. Dose dependent sedation was the principal dose limiting adverse effects of tetrabenazine. Common symptoms were hypoactivity, lethargy, strabismus, tremor, and convulsions. Histopathological changes consistent with elevated prolactin in female rats included mammary gland hyperplasia and changes in reproductive tissues.

Tetrabenazine and its metabolites accumulate in melanin-containing tissues in partially pigmented rats. The clinical relevance of this finding is unknown.

Tetrabenazine and its metabolites α-HTBZ and β-HTBZ were not mutagenic in the in vitro bacterial reverse mutation assay but were clastogenic in the in vitro chromosome aberration assay. Tetrabenazine was not genotoxic in vivo in male mice and rats but produced equivocal results in female rats. Tetrabenazine did not cause an increase in any tumour type when administrated for 26 weeks in the transgenic p53 heterozygous mouse model at doses up to 30 mg/kg/day. In a limited study in male rats tetrabenazine was noncarcinogenic when administered for 94 weeks at doses up to 12 mg/kg/day.

In a fertility and early embryonic development study at systemic exposures below those observed clinically there was no evidence of effect on pregnancy or in utero survival in rats. Length of the estrous cycle was increased and a delay in fertility was seen in female rats. Reproduction was unaffected in male rats.

In embryo-fetal developmental toxicity studies there was no evidence of embryotoxicity or teratogenicity in either rats or rabbits. In a perinatal and postnatal study in rats, neonatal deaths and delayed pup maturation were observed at systemic exposures below those observed clinically. These effects could either be indirect effects due to inadequate maternal care or a direct effect of tetrabenazine on the pups.