Antioxidant with free radical scavenging activity; cytoprotective effects on gastrointestinal mucosa (mechanism not fully quantified) [1]
Inhibitor of hepatic stellate cell (HSC) activation and hepatocellular carcinoma proliferation (mechanism not fully quantified) [2]

Polaprezinc (8-16 μg/ml) significantly inhibited proliferation of LX-2 hepatic stellate cells after 3 days (vs. 0 μg/ml: Day 3, P=0.0025; Day 4, P<0.0001). No dose-dependent effect was observed between 8 and 16 μg/ml. [2]

In hepG2 and huh7 hepatocellular carcinoma cells, Polaprezinc (8-16 μg/ml) reduced proliferation after 5 days (hepG2: Day 5, P=0.0033; Day 6, P<0.0001). Colony formation assays confirmed dose-dependent inhibition (hepG2: 16 μg/ml, P<0.0001; huh7: 16 μg/ml, P<0.0001). [2]

Transwell migration assays showed Polaprezinc (8 μg/ml) reduced LX-2 cell migration by ~50% (P=0.0082), indicating suppression of HSC motility. [2]

RT-qPCR analysis revealed Polaprezinc (8 μg/ml) downregulated fibrotic markers in LX-2 cells: Collagen I (P<0.0001), fibronectin (P=0.0008), and α-SMA (P=0.0004). [2]

A chelate molecule consisting of zinc ions, L-carnosine, β-alanine dipeptide, and L-histidine, Polaprezinc (PZ) is an anti-ulcer medication. Polaprezinc scavenges free radicals and has antioxidant properties. In animal models, polaprezinc has been demonstrated to be efficacious against acute radiation proctitis and to have anti-inflammatory properties following radiation exposure [1].

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In C57BL/6J mice receiving 15 Gy total body irradiation (TBI), oral pretreatment with Polaprezinc (100 mg/kg) 2 hours prior to radiation significantly increased viable crypt counts vs. post-treatment or untreated controls: Duodenum – 39.8 vs. 20.2 (P=0.04); Ileum – 66.1 vs. 43 (P=0.02). Pre-irradiation administration showed superior radioprotection. [1]

After 2 Gy TBI, Polaprezinc pretreatment reduced apoptosis in intestinal crypts at 8 hours (peak apoptosis time): Apoptotic index decreased by 61% in duodenum (0.022 vs. 0.056), 58% in jejunum (0.044 vs. 0.106, P=0.01), and 38% in ileum (0.052 vs. 0.084). [1]

Radiation-induced apoptosis predominantly occurred at positions 1-10 from crypt base (stem cell zone). Polaprezinc reduced apoptotic cells at these critical positions across duodenum, jejunum, and ileum (Fig. 5). [1]

Cell proliferation assay: LX-2, hepG2, or huh7 cells seeded in 96-well plates (1×10³/well) with RPMI 1640 + 10% FBS. Treated with 0/8/16 μg/ml Polaprezinc. MTS reagent added daily, incubated 4 h at 37°C. Absorbance measured at 490 nm for 6 consecutive days. [2]

Colony formation assay: 500 cells/well seeded in 24-well plates. After 14-day incubation, cells fixed with methanol, stained with 0.1% crystal violet. Colonies (>300 cells) counted under inverted microscope. [2]

Migration assay: 5×10⁴ LX-2 cells in serum-free medium added to Transwell upper chamber. Lower chamber contained RPMI 1640 + 15% FBS. After 24 h incubation, migrated cells fixed/stained with crystal violet and counted. [2]

RT-qPCR: LX-2 cells treated with 0/8 μg/ml Polaprezinc for 7 days. RNA extracted, reverse-transcribed to cDNA. Collagen I, fibronectin, α-SMA expression analyzed via SYBR Green PCR using GAPDH normalization. Cycling: 95°C 10 min → 40 cycles (95°C 15 sec → 60°C 30 sec → 72°C 30 sec). [2]

Crypt survival assay: Mice received oral Polaprezinc (100 mg/kg in drinking water) 2 hours before or after 15 Gy TBI. Tissues (duodenum, jejunum, ileum) harvested 3 days post-irradiation, fixed, H&E-stained, and viable crypts (≥10 cells/cross-section) counted. [1]

Apoptosis kinetics assay: Polaprezinc administered 2 hours before 2 Gy TBI. Duodenum, jejunum, ileum, and rectum harvested at 0, 4, and 8 hours post-IR. Apoptotic cells identified by H&E-stained fragments; apoptotic index and cell position recorded. [1]

Absorption, Distribution and Excretion
Sano et al. investigated the intestinal absorption of L-CAZ in rats using compounds labeled with 14C and 65Zn. They proposed that L-CAZ dissociates into its constituents L-carnosine and zinc during intestinal absorption. This study used compounds labeled with 14C and 65Zn to examine the intestinal absorption of this drug. Paleprozinc is metabolized into its constituents L-carnosine and zinc during intestinal absorption. The study found that after a single administration of 14C-labeled L-CAZ to rats, the excretion rate was 4.1% in urine, 13.3% in feces, and 38.8% in exhalation. The study using 65Zn-labeled Paleprozinc showed an excretion rate of 0.3% in urine and 85.0% in feces. The zinc absorption rate was estimated to be approximately 11%.

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Metabolism/Metabolites
Following a single dose in rats, the excretion rates of pipprecinol zinc were: 4.1% in urine, 13.3% in feces, and 38.8% in exhalation when using 14C-labeled pipprecinol; and 0.3% in urine and 85.0% in feces when using 65Zn-labeled L-CAZ. The zinc absorption rate is estimated to be approximately 11%.

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Biological Half-Life
Studies in rats have shown that the half-life of pipprecinol zinc is approximately 2 hours.

Protein Binding
It has been observed that a high-protein diet accelerates zinc absorption, meaning that low-molecular-weight amino acids may carry zinc into the circulatory system through complexation.

[1]. Polaprezinc protects normal intestinal epithelium against exposure to ionizing radiation in mice. Mol Clin Oncol. 2016 Oct;5(4):377-381.

Polaprezinc is a chelate of zinc and L-carnosine. It was the first zinc-related drug approved in Japan and has been used clinically to treat gastric ulcers. Studies have shown that Polaprezinc may be effective in treating pressure ulcers. A 2013 study indicated that Polaprezinc, in combination with aspirin, may be effective in combating small intestinal mucosal damage caused by long-term aspirin use. Polaprezinc is an orally bioavailable zinc and L-carnosine chelate with potential gastric protective, antioxidant, anti-ulcer, and anti-inflammatory activities. After administration, Polaprezinc can increase the expression of various antioxidant enzymes in the gastric mucosa, such as superoxide dismutase 1 (SOD-1), SOD-2, heme oxygenase-1 (HO-1), glutathione S-transferase (GST), glutathione peroxidase (GSH-px), peroxide reductase-1 (PRDX1; PRXI), and PRXD5 (PRXV), which protect cells from damage by reactive oxygen species (ROS). In addition, this drug can inhibit the activity of the transcription factor nuclear factor-κB (NF-κB) and reduce the expression of various pro-inflammatory cytokines, such as interleukin (IL) 1β, IL-6, IL-8, and tumor necrosis factor-α (TNF-α). P-preparizumab can also increase the expression of various growth factors, such as platelet-derived growth factor-B (PDGF-B), vascular endothelial growth factor (VEGF), and nerve growth factor (NGF), as well as various heat shock proteins (HSPs), including HSP90, HSP70, HSP60, HSP47, HSP27, and HSP10. This can protect the gastric mucosa from damage and accelerate its healing.

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Indications
Peptic ulcers, dyspepsia.

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Mechanism of Action
Polyprezinc increases the expression of multiple antioxidant enzymes, including superoxide dismutase 1 (SOD-1), SOD-2, heme oxygenase-1 (HO-1), glutathione S-transferase (GST), glutathione peroxidase (GSH-px), peroxide reductase-1 (PRDX1; PRXI), and PRXD5 (PRXV). This process occurs in the gastric mucosa, protecting mucosal cells from reactive oxygen species. The drug inhibits the activity of the transcription factor nuclear factor-κB (NF-κB) and reduces the expression of multiple inflammatory cytokines, including interleukin (IL) 1β, IL-6, IL-8, and tumor necrosis factor-α (TNF-α). In addition, Polaprezinc promotes the expression of a variety of growth factors, including platelet-derived growth factor-B (PDGF-B), vascular endothelial growth factor (VEGF), and nerve growth factor (NGF), as well as a variety of heat shock proteins (HSPs), such as HSP90, HSP70, HSP60, HSP47, HSP27, and HSP10. This process promotes tissue growth and protects the gastric mucosa from damage. Polaprezinc is an anti-ulcer drug with proven antioxidant and free radical scavenging properties. It protects the intestinal epithelium from radiation damage by inhibiting apoptosis, particularly in the crypt stem cell region. [1]
Its mechanism may involve inhibition of the p53/p21/Bax pathway (cited from previous studies) and reduction of oxidative stress. Administration 2 hours before irradiation is crucial for efficacy, which coincides with the gastrointestinal transit time in mice. [1]
Main application: Prevention of radiation gastrointestinal toxicity during abdominal/pelvic radiotherapy. Clinical studies have shown that it does not interfere with the tumor’s response to radiation. [1]

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Polaprezinc reverses liver fibrosis by inactivating hepatic stellate cells (HSCs): inhibiting proliferation/migration and downregulating extracellular matrix (ECM) markers (type I collagen, fibronectin, α-SMA). Gene ontology analysis of HepG2 cells treated with 16 μg/ml polaprezinc revealed that the expression of 202 genes involved in the regulation of cytoskeleton organization, cell movement and proliferation was altered (>1.5-fold). [2]
Speculated mechanism: Targeted activation of hepatic stellate cells (HSCs) and disruption of the tumor microenvironment. Clinical significance: May become a novel treatment for patients with hepatocellular carcinoma (HCC) complicated with cirrhosis. [2]

C9H12N4O3ZN

289.6

288.02

C, 37.33; H, 4.18; N, 19.35; O, 16.57; Zn, 22.58

107667-60-7

51051629

White to off-white solid powder

557.6ºC at 760 mmHg

300ºC

291ºC

3

6

4

17

265

1

O=C1[C@@H]([N-](C2=O)[Zn+2](NCC2)[O-]1)CC3=CN=CN3

GFWBKUDRXMQSFD-FJXQXJEOSA-M

InChI=1S/C9H14N4O3.Zn/c10-2-1-8(14)13-7(9(15)16)3-6-4-11-5-12-6;/h4-5,7H,1-3,10H2,(H3,11,12,13,14,15,16);/p-1/t7-;/m0./s1

3-aminopropanoyl-[(1S)-1-carboxy-2-(1H-imidazol-5-yl)ethyl]azanide;zinc

Z 103; Polaprezinc; 107667-60-7; Zinc L-carnosine; DTXSID7048615; beta-alanyl-L-histidinato zinc; NCGC00181764-01; CHEMBL3184454; DTXCID4028541; Polaprezinc

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

H2O : ~3.37 mg/mL (~11.68 mM)
DMSO :< 1 mg/mL

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)