Source: Medicines and Medical Devices Safety Authority (NZ) Revision Year: 2019 Publisher: Douglas Pharmaceuticals Ltd, P O Box 45 027, Auckland 0651, New Zealand, Phone: (09) 835 0660
Pharmacotherapeutic group: Nervous system drugs
ATC code: N07XX06
Tetrabenazine is a synthetic derivative of benzylquinolizine that causes depletion of dopamine and other monoamines in the central nervous system.
Studies conducted in vitro 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 dihydrotetrabenazine, the principal metabolite of tetrabenazine, has a similar affinity and more significant selectivity for VMAT2.
At a synaptic level tetrabenazine creates a reversible depletion of monoamines in the presynaptic vesicles. Within the CNS tetrabenazine causes preferential depletion of dopamine from nerve terminals but neurotransmitter depletion by a single dose of tetrabenazine is reversible and lasts only a few hours. This feature differentiates the drug from reserpine, a drug that causes long lasting monoamine depletion. This pharmacological effect explains the therapeutic benefit of tetrabenazine is patients' suffering from hyperkinetic movement disorders.
Tetrabenazine is quickly and mostly absorbed after oral administration. Its absorption is not affected by the taking of food.
After administration of single doses from 12.5 to 50 mg of tetrabenazine, the maximum plasma concentration and the area under the curve increased in proportion to the dose, indicating a linear kinetic.
Clinical testing has shown that a single oral dose of tetrabenazine undergoes extensive (>75%) absorption from the gastro-intestinal tract. The metabolism of tetrabenazine is complex, initially proceeding via the formation of alpha and beta dihydrotetrabenazine. The majority of the observed metabolites appear to be formed from these dihydrotetrabenazines as a result of Odealkylation, hydroxylation and conjugation.
No significant build-up has been observed after daily administration. The elimination half-life of dihydrotetrabenazine is approximately five hours.
Tetrabenazine is mostly eliminated in metabolised form in urine (less than 2% of tetrabenazine is excreted in unchanged form).
In repeated dose toxicity studies orally administered tetrabenazine is generally well tolerated across all animal species tested. Most effects observed are related to the pharmacological parameters of the drug and reflect central monoamine depletion. These signs typically include hypoactivity, lethargy, squinted eyes, or eyes closed. They last up to several hours after dosing and in some species at high doses interfere with normal food intake with consequent decreased or suppressed body weight gain. Across all animal species tested dose-dependent sedation is the dose limiting effect and the principal adverse effect following oral administration of tetrabenazine.
The standard battery of genotoxicity studies was conducted with tetrabenazine, and no mutagenic effects were found in the bacterial reverse mutation assay. For the in vitro mammalian chromosome aberration test (CHO cells), tetrabenazine was cytotoxic and clastogenic at toxic levels. The positive response was noted only in the presence of S9 mix at tetrabenazine concentrations that were toxic to the cells. However, in the in vivo mammalian erythrocyte micronucleus test (rats), tetrabenazine was not clastogenic at the maximum tolerated dose (100 mg/kg/day).
In the developmental toxicity tests, there was no evidence of in utero mortality, growth retardation or teratogenicity in either rats or rabbits. In the perinatal and postnatal study in rats, neonatal deaths were observed. However, based on the inadequate maternal care observed in the dams and the pattern of pup deaths the effects noted in this study are attributable to inadequate maternal care at or just after birth rather than to a direct effect on any developmental or reproductive parameter.
No carcinogenicity studies have been conducted on tetrabenazine.
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