Ziprasidone HCl

Ziprasidone Hydrochloride (CAS No. 122883-93-6) is a second-generation antipsychotic agent with antitumor activity. Its core targets include dopamine D₂/D₃ receptors, serotonin 5-HT₂A/5-HT₂C/5-HT₁A/5-HT₁D receptors, α₁-adrenergic receptors, and glutamic-oxaloacetic transaminase 1 (GOT1, which it inhibits non-competitively).

Key concentration data are as follows: the half-maximal inhibitory concentration (IC₅₀) for GOT1 inhibition is 5.39±1.13 μM; the antiproliferative IC₅₀ values against pancreatic cancer SW1990 cells, BxPC-3 cells, and fibrosarcoma HT1080 cells are 26.71±1.16 μM, 12.19±0.19 μM, and 14.04±1.10 μM, respectively; the dissociation constant (Kd) for binding to GOT1 is 89.30±5.35 μM.

Common concentrations for laboratory use: 10–40 μM for in vitro cell experiments (to induce tumor cell apoptosis and inhibit migration); 100 μg/mL for Caco-2 cell permeability studies; for animal experiments, oral administration of 100–200 mg/kg is used in pancreatic cancer xenograft models.

The clinically effective therapeutic concentration corresponds to the following oral dosage: for the treatment of schizophrenia and bipolar disorder, the maximum dose is 80 mg per administration, twice daily. When formulated as nanocrystals or solid dispersions and administered on an empty stomach, its bioavailability is twice that of the marketed product, and the impact of food on absorption is eliminated. The antitumor clinical application is still under research, with reference doses based on animal experiments (100–200 mg/kg).

Its biological activities are manifested in regulating neurotransmitter receptors to ameliorate psychiatric symptoms, and inhibiting GOT1 to interfere with glutamine metabolism and disrupt tumor redox balance, thereby suppressing the proliferation and migration of pancreatic cancer cells. It has a favorable safety profile, with no significant cardiotoxicity observed in cases of overdose. Mild weight loss is occasionally reported in high-dose animal experiments. It is indicated for the treatment of schizophrenia and bipolar disorder, and holds potential for pancreatic cancer therapy.

References:

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[2] Xue X, Chen G, Xu X, Wang J, Wang J, Ren L. A Combined Utilization of Plasdone-S630 and HPMCAS-HF in Ziprasidone Hydrochloride Solid Dispersion by Hot-Melt Extrusion to Enhance the Oral Bioavailability and No Food Effect. AAPS PharmSciTech. 2019 Jan 2;20(1):37. doi: 10.1208/s12249-018-1216-8. PMID: 30604142.

[3] Karaküçük A, Taşhan E, Öztürk N, Çelebi N. In Vitro Caco-2 Cell Permeability Studies of Ziprasidone Hydrochloride Monohydrate Nanocrystals. Turk J Pharm Sci. 2021 Apr 20;18(2):223-227. doi: 10.4274/tjps.galenos.2020.67366. PMID: 33902264; PMCID: PMC8100775.

[4] Murkute SR, Singh GP, Vasantharaju SG, Bhat K, Godbole HM, Upadhyay PR, Trivedi A. Identification of Novel Impurity of Ziprasidone. J Pharm Biomed Anal. 2022 Jan 5;207:114416. doi: 10.1016/j.jpba.2021.114416. Epub 2021 Oct 7. PMID: 34678557.

[5] Yang Y, Zheng M, Han F, Shang L, Li M, Gu X, Li H, Chen L. Ziprasidone suppresses pancreatic adenocarcinoma cell proliferation by targeting GOT1 to trigger glutamine metabolism reprogramming. J Mol Med (Berl). 2022 Apr;100(4):599-612. doi: 10.1007/s00109-022-02181-8. Epub 2022 Feb 25. PMID: 35212782.