Pharmacodynamics
Mechanism of Action:
The exact mechanism by which ZONALTA exerts its therapeutic effects have not been established in Bipolar I disorder.
However, the efficacy of ZONALTA could be mediated through inhibition of Protein Kinase C (PKC).1
Protein Kinase C (PKC):2
- It represents a family of enzymes highly enriched in the brain, where it plays a major role in regulating both pre-synaptic and post-synaptic aspects of neurotransmission.
- PKC plays a crucial role in the regulation of neuronal excitability, neurotransmitter release, regulation of synaptic plasticity and various forms of learning and memory.
- Excessive activation of PKC results in symptoms related to bipolar I disorder.
ZONALTA directly inhibits PKC activity in concentration dependent manner. The percentage PKC inhibition ranged between 12% and 78% with ZONALTA concentration between 0.025 and 0.2 mM, respectively.3
5-hydroxytryptamine; AMPA: Alpa-amino-3-hydroxyl-5-methyl-4-isoxazolepropionic acid; DA: Dopamine; DAG: Diacetylglycerol; GLU: Glutamate; GAP: Growth-associated protein of 43 kDa;IP3: Inositol 1,4,5-triphosphate; MARCKS: Myristoylated alanine-rich C-kinase substrate; NA: Noradrenaline; NMDA: N-methyl-D-aspartate; PIP2: phosphatidylinositol-4,5-bisphosphate;PKC: Protein Kinase C; PLC: Phospholipase-C; SNAP-25: Synaptosomal-associated protein 25; Zarate CA, et al. CNS Drugs. 2009;23(7):569-82.
Pharmacokinetics4
Orally administered ZONALTA is rapidly absorbed and systemically available.
The time to peak (Tmax) is between 4.5 and 6 hours after oral administration.
ZONALTA is not metabolized by Cytochrome P450 enzymes.
Half-life (t½): 52.1–58.1 hours
References
- 1. ZONALTA (endoxifen citrate) tablets 8 mg. Prescribing information. Intas Pharmaceuticals LTD.
- 2. Zarate CA, Manji HK. Protein kinase C inhibitors: rationale for use and potential in the treatment of bipolar disorder. CNS Drugs. 2009;23(7):569–82.
- 3. Ali SM, Ahmad A, Shahabuddin S, Ahmad MU, Sheikh S, Ahmad I. Endoxifen is a new potent inhibitor of PKC: a potential therapeutic agent for bipolar disorder. Bioorg Med Chem Lett. 2010 Apr;20(8):2665–7.
- 4. Ahmad A, Shahabuddin S, Sheikh S, Kale P, Krishnappa M, Rane RC, et al. Endoxifen, a new cornerstone of breast cancer therapy: demonstration of safety, tolerability, and systemic bioavailability in healthy human subjects. Clinical Pharmacology & Therapeutics. 2010;88(6):814–7.