- Cytochrome P450 enzyme substrate: CYP2D6 and CYP3A4, CYP1A2
- Action to be taken: Caution with close monitoring for side effects.
- Rationale: α -HTBZ and β-HTBZ (major metabolites)are formed by carbonyl reductase that occurs mainly in the liver. α-HTBZ is O-dealkylated by CYP450 enzymes, principally CYP2D6, with some contribution of CYP1A2. β-HTBZ is O-dealkylated principally by CYP2D6. P1A2, CYP2A6, CYP2C9, CYP2C19, and CYP2E1 do not play a major role in metabolism of α-HTBZ or β-HTBZ based on in vitro studies. The results of in vitro studies do not suggest that tetrabenazine, α-HTBZ, orβ-HTBZ are likely to result in clinically significant inhibition of CYP2D6, CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2E1, or CYP3A. Their effect on CYP2B6 has not been evaluated. In vitro studies suggest that neither tetrabenazine nor itsα- orβ-HTBZ metabolites is likely to result in clinically significant induction of CYP1A2, CYP3A4, CYP2B6, CYP2C8, CYP2C9, or CYP2C19. Neither tetrabenazine nor its metabolites is likely to be a substrate or inhibitor of P-glycoprotein at clinically relevant concentrationsin vivo. In vitro studies have shown that cannabis is metabolized by CYP450 enzymes, mainly by CYP3A4 and CYP2C19. Furthermore, various in vitro studies have found cannabinoids to be weak inhibitors of CYP enzymes. However other studies have shown that CBD is a potent inhibitor of CYP3A4 and CYP2C19 A strong CYP2D6 inhibitor (paroxetine) markedly increases exposure to Tetrabenazine metabolites.
- Xenazine(tetrabenazine) package insert. Prestwick Pharmaceuticals Inc. Washington DC. 2008
- Watanabe K, Yamaori S, Funahashi T, et al. Cytochrome P450 enzymes involved in the metabolism of tetrahydrocannabinols and cannabinol by human hepatic microsomes. Life Sci. 2007;80:1415-1419.
- Stout SM, Cimino NM. Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review. Drug Metab Rev. 2014;46:86-95.
- Yamaori S, Ebisawa J, Okushima Y, Yamamoto I, Watanabe K. Potent inhibition of human cytochrome P450 3A isoforms by cannabidiol: Role of phenolic hydroxyl groups in the resorcinol moiety. Life Sciences. 2011;88:730-736.