About this pathway
Background
Brexpiprazole (OPC-34712, IUPAC name: (7-{4-(4-(1-benzothiophen-4-yl)piperazin-1-yl)butyloxy}quinoline-2(1H)-one)) is an atypical antipsychotic drug approved for the treatment of schizophrenia in more than 60 countries, including the United States, Canada, Australia, Europe and Japan [Articles:40157325, 28750151, 33663326]. In the United States, it was approved by the Food and Drug Administration (FDA) in July 2015 as an adjunctive treatment for major depressive disorder (MDD) [Articles:28750151, 34328221, 36350097, 31560202].
Pharmacodynamics
Brexpiprazole is an effective serotonin-dopamine activity modulator. It operates as a partial agonist at the serotonin 5-HT1A (HTR1A) and dopamine D2 (DRD2) receptors, while also acting as an antagonist at the serotonin 5-HT2A (HTR2A) and noradrenaline α1B/2C receptors (ADRA1B/ADRA2C), exhibiting similar levels of potency [Articles:40157325, 28750151, 34328221, 33663326, 36350097, 31560202].
Pharmacokinetics
Brexpiprazole is primarily metabolized via the cytochrome P450 (CYP) pathway. CYP2D6 and CYP3A4 account for approximately 46.7% and 43.3% respectively of brexpiprazole's S-oxidation into its primary metabolite, brexpiprazole S-oxide (also known as DM-3411) [Articles:28750151, 40157325, 34328221, 31560202]. The metabolic rate of CYP3A4 influences the systemic clearance and plasma levels of brexpiprazole, potentially resulting in a diminished therapeutic effect [Article:31560202]. The biotransformation of brexpiprazole into its minor metabolite, DM-3412, is mainly mediated by CYP2D6 [Article:36350097]. Brexpiprazole S-oxide accounts for 45-70% of brexpiprazole exposure in plasma; however, it has significantly less pharmacological potency in comparison to brexpiprazole itself [Article:33663326]. Furthermore, neither brexpiprazole S-oxide nor DM-3412 appears to cross the blood-brain barrier easily, indicating that they likely do not contribute to the drug's pharmacological effects [Articles:28750151, 33663326].
Pharmacogenomics
Patients who are classified as poor metabolizers (PMs) of CYP2D6 may experience higher plasma concentrations of brexpiprazole compared to those with normal CYP2D6 metabolism (NMs). The labels from the FDA, EMA, HCSC, and Swissmedic for brexpiprazole all advise reducing the dose to half of the usual amount for PMs and for patients taking concomitant CYP3A4 inhibitors, CYP2D6 inhibitors, or strong CYP3A4 inducers [Article:34328221], brexpiprazole prescribing info. The study of Ishigooka et al., evaluated the pharmacokinetics and safety of brexpiprazole in a cohort of Japanese patients with schizophrenia. According to their findings, intermediate metabolizers (IMs) of CYP2D6 (AS0.25-AS0.75) were associated with higher dose-adjusted brexpiprazole AUC and Cmax and lower clearance compared to IMs+NMs of CYP2D6 (AS1-AS2), whereas the brexpiprazole half-life time was not significantly associated [Article:28750151]. Genetic variability in CYP3A4 has also been linked to adverse side effects, like nasopharyngitis and worsening of psychotic symptoms and the inefficacy of brexpiprazole. Research by Chen et al. indicated that mutations occurring near the active site of CYP3A4, such as CYP3A4*17, may result in a loss of enzymatic activity. In contrast, variants located farther from the active site, like CYP3A4*19, may have little impact on the function of CYP3A4 [Article:31560202].
Reactions & interactions (5)
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Biochemical Reaction
brexpiprazole → brexpiprazole S-oxide
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Biochemical Reaction
brexpiprazole → brexpiprazole DM-3412
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Catalysis
CYP3A4 → Biochemical Reaction
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Catalysis
CYP2D6 → Biochemical Reaction
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Catalysis
CYP2D6 → Biochemical Reaction
Edit history (3)
- 2023-03-14 Create
- 2023-06-19 Update Added figure, summary.
- 2025-07-07 Update Added the description