Dopamine D₂ receptor antagonist [2]
.
- Acetylcholinesterase inhibitor [2]
.

The prokinetic action of icopride hydrochloride is regulated by the antagonistic effect on dopamine D2 receptors and the inhibitory effect on AChE in both the colon and the ileum [3]. In the ileum of guinea pigs, itopride hydrochloride (0.1 nM-1 μM) dramatically increases the rate of peristalsis propagation [3].

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Effect on Ileal Peristaltic Contraction Amplitude: In isolated guinea pig distal ileum, itopride (10⁻¹⁰ - 10⁻⁶ M) infusion increased the amplitude of peristaltic contraction, but the change was not statistically significant. When administered after dopamine (10⁻⁸ M), itopride (10⁻⁷ M) increased the amplitude, but again without statistical significance. Itopride (10⁻⁷ M) added to acetylcholine (ACh, 10⁻⁸ M) further increased the amplitude, but this was also not statistically significant [3]
.
- Effect on Ileal Peristaltic Propagation Velocity: Itopride (10⁻¹⁰ - 10⁻⁶ M) significantly and dose-dependently accelerated the propagation velocity of peristaltic contractions in the guinea pig ileum (p < 0.05). Dopamine (10⁻⁸ M) significantly decelerated the velocity to 81.3 ± 5.4% of control, and this effect was significantly reversed by the administration of itopride (10⁻⁷ M), which increased the velocity to 109.3 ± 3.86% (p < 0.05) [3]
.
- Effect on Colonic Transit Time: In isolated guinea pig distal colon, itopride (10⁻¹⁰ - 10⁻⁶ M) significantly and dose-dependently shortened colonic transit time (p < 0.05). Dopamine (10⁻⁸ M) significantly delayed colonic transit time to 114.6 ± 9.3% of control, and this delay was significantly reversed by the administration of itopride (10⁻⁷ M), which shortened transit time to 80.1 ± 9.0% (p < 0.05). Acetylcholine (10⁻⁸ M) shortened colonic transit time, but the addition of itopride did not produce an additive effect [3]
.
- Comparison with Neostigmine: Neostigmine (10⁻¹⁰ - 10⁻⁷ M) was used as a reference AChE inhibitor. In the ileum, neostigmine significantly accelerated propagation velocity only at lower concentrations (10⁻¹⁰ - 10⁻⁹ M) and decreased it at higher concentrations (10⁻⁸ - 10⁻⁷ M) (p < 0.05). In the colon, neostigmine significantly shortened transit time only at higher concentrations (10⁻⁸ - 10⁻⁷ M) (p < 0.05). This pattern differs from the consistent dose-dependent effects of itopride [3]
.

In comparison to the vehicle group, itopride hydrochloride (30 mg/kg; oral) dramatically accelerated stomach emptying [4]. Oral ilopride hydrochloride (30 mg/kg) exhibits a T1/2 of 24.9 min and a Cmax of 358 ‰ [4].

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Study Design and Patient Population: A prospective, randomized, open-label pilot study was conducted to evaluate the efficacy and dose-response of itopride in patients with mild GERD. Twenty-six patients (age 18-65 years) with GERD symptoms, endoscopic evidence of mild esophagitis (Savary-Miller grade I or II), and abnormal 24-h esophageal pH monitoring (total acid exposure time >5% with pH<4) were enrolled. Patients were randomly assigned to receive either 150 mg/day (50 mg three times daily) or 300 mg/day (100 mg three times daily) of itopride for 30 days [2]
.
- Effect on GERD Symptoms: Treatment with itopride significantly improved GERD symptoms. The mean heartburn score decreased significantly in both the 150 mg group (P<0.0001) and the 300 mg group (P=0.0006) compared to pretreatment. The total symptom score was also significantly reduced in both groups after treatment (P<0.0001). There was no statistically significant difference in symptom improvement between the two dose groups [2]
.
- Effect on Esophageal Acid Reflux Variables: In the 300 mg group, itopride treatment significantly improved several objective measures of acid reflux as assessed by 24-h pH monitoring. Specifically, there was a significant decrease in total time with pH<4 (P=0.011), percent time with pH<4 (P=0.005), and DeMeester score (P=0.007) compared to pretreatment values. In the 150 mg group, itopride significantly reduced the duration of the longest reflux episode (P=0.018) [2]
.
- Safety and Tolerability: Itopride was well tolerated in both dose groups. No serious adverse effects were observed. There were no significant changes in mean serum prolactin levels after 4 weeks of treatment in either group. Although two patients in the 300 mg group showed prolactin levels exceeding 15 mg/mL, no clinical adverse events such as galactorrhea were reported [2]
.

Animal/Disease Models: Male ddY strain mouse (23.7-28.5 g) [2]
Doses: 3 mg/kg, 10 mg/kg, 30 mg/kg
Route of Administration: Oral
Experimental Results:Accelerated gastric emptying at 30 mg/kg dose .

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Animal/Disease Models: Male ddY strain mouse (23.7-28.5 g) [2]
Doses: 3 mg/kg, 10 mg/kg, 30 mg/kg (pharmacokinetic/PK/PK analysis)
Route of Administration: Oral
Experimental Results:Cmax (358 ‰), T1 /2 (24.9 minutes), dose 30 mg/kg.

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Ileal Peristalsis Assay (Ex Vivo):** Male Hartley guinea pigs (~300 g) were euthanized by a blow to the occipital region and severing the carotid arteries. The distal ileum (15 cm from the ileocecal junction) was excised, cleaned, and placed in a bath containing Krebs-Henseleit (K-H) solution (95% O₂/5% CO₂, 37°C). The mechanical activity of the circular muscle was monitored using three clips attached to the serosal surface at 2.5 cm intervals, connected to independent tension transducers (initial tension set to 1 g). Tissues were equilibrated for 60 minutes. Peristalsis was induced by pumping K-H solution (0.4 mL/min) into the lumen for 20 minutes. Itopride (10⁻¹⁰ - 10⁻⁶ M) was added to the bath and lumen cumulatively without washing between concentrations. Peristaltic activity was assessed by measuring the amplitude and propagation velocity (distance from oral to anal side divided by time). Additional experiments were conducted with neostigmine (10⁻¹⁰ - 10⁻⁷ M), dopamine (10⁻⁸ M), and ACh (10⁻⁸ M), followed by itopride (10⁻⁷ M) [3]
.
- **Colonic Transit Assay (Ex Vivo):** The distal colon (~10 cm from the anus) was excised from guinea pigs, cleaned, and placed in a K-H solution bath (95% O₂/5% CO₂, 37°C). Both ends were connected to the chamber. After 60 minutes stabilization, artificial feces (10 mm length, 4 mm width) were inserted into the oral side of the lumen, and K-H solution was pumped (0.4 mL/min) to propel the artificial feces. The time required to move the artificial feces over a total length of 10 cm (measured at 2 cm intervals) was recorded as colonic transit time. After control measurements, itopride (10⁻¹⁰ - 10⁻⁶ M) was applied cumulatively to the bath and lumen. Additional experiments were performed with neostigmine (10⁻¹⁰ - 10⁻⁷ M), dopamine (10⁻⁸ M), and ACh (10⁻⁸ M), followed by itopride (10⁻⁷ M) [3]
.

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Ileal Peristalsis Assay (Ex Vivo): Male Hartley guinea pigs (~300 g) were euthanized by a blow to the occipital region and severing the carotid arteries. The distal ileum (15 cm from the ileocecal junction) was excised, cleaned, and placed in a bath containing Krebs-Henseleit (K-H) solution (95% O₂/5% CO₂, 37°C). The mechanical activity of the circular muscle was monitored using three clips attached to the serosal surface at 2.5 cm intervals, connected to independent tension transducers (initial tension set to 1 g). Tissues were equilibrated for 60 minutes. Peristalsis was induced by pumping K-H solution (0.4 mL/min) into the lumen for 20 minutes. Itopride (10⁻¹⁰ - 10⁻⁶ M) was added to the bath and lumen cumulatively without washing between concentrations. Peristaltic activity was assessed by measuring the amplitude and propagation velocity (distance from oral to anal side divided by time). Additional experiments were conducted with neostigmine (10⁻¹⁰ - 10⁻⁷ M), dopamine (10⁻⁸ M), and ACh (10⁻⁸ M), followed by itopride (10⁻⁷ M) [3]
.
- Colonic Transit Assay (Ex Vivo): The distal colon (~10 cm from the anus) was excised from guinea pigs, cleaned, and placed in a K-H solution bath (95% O₂/5% CO₂, 37°C). Both ends were connected to the chamber. After 60 minutes stabilization, artificial feces (10 mm length, 4 mm width) were inserted into the oral side of the lumen, and K-H solution was pumped (0.4 mL/min) to propel the artificial feces. The time required to move the artificial feces over a total length of 10 cm (measured at 2 cm intervals) was recorded as colonic transit time. After control measurements, itopride (10⁻¹⁰ - 10⁻⁶ M) was applied cumulatively to the bath and lumen. Additional experiments were performed with neostigmine (10⁻¹⁰ - 10⁻⁷ M), dopamine (10⁻⁸ M), and ACh (10⁻⁸ M), followed by itopride (10⁻⁷ M) [3]
.

Adverse Events: Only minor adverse events were reported. The drug was well tolerated [2]
.
- Prolactin Levels: No significant change in mean serum prolactin levels was observed in either dose group after 4 weeks of treatment. In the 300 mg group, two patients had prolactin levels increase above 15 mg/mL, but this was not associated with any clinical adverse events like galactorrhea [2]
.
- Extrapyramidal Symptoms: No extrapyramidal symptoms were observed in either dose group [2]
.
- Laboratory Tests: Routine blood biochemistry, complete blood count, and urinalysis showed no clinically significant changes related to itopride treatment [2]
.

[1]. A novel water-soluble dopamine-2 antagonist with anticholinesterase activity in gastrointestinal motor activity. Comparison with domperidone and neostigmine. Gastroenterology. 1990 Aug;99(2):401-8.

[2]. Effect of itopride, a new prokinetic, in patients with mild GERD: a pilot study. World J Gastroenterol. 2005 Jul 21;11(27):4210-4.

[3]. Effect of Itopride Hydrochloride on the Ileal and Colonic Motility in Guinea Pig In Vitro. Effect of Itopride Hydrochloride on the Ileal and Colonic Motility in Guinea Pig In Vitro. Yonsei Med J. 2008 Jun 30;49(3):472-8.

[4]. Validation of 13 C-Acetic Acid Breath Test by Measuring Effects of Loperamide, Morphine, Mosapride, and Itopride on Gastric Emptying in Mice. Biol Pharm Bull. 2008 Oct;31(10):1917-22.

Drug Class and Mechanism of Action: Itopride is a newly developed prokinetic agent with a dual mechanism of action. It acts as a dopamine D₂ receptor antagonist and an acetylcholinesterase inhibitor. This combination enhances gastric motility by potentiating acetylcholine effects on gastrointestinal smooth muscle while counteracting dopamine-mediated inhibition [2]
.
- Pharmacodynamic Effects: Itopride accelerates gastric emptying, improves gastric tension and sensitivity, and has anti-emetic properties. It has been shown to have equivalent efficacy to cisapride in the treatment of functional dyspepsia [2]
.
- Clinical Indication Studied: This pilot study investigated the efficacy of itopride in patients with mild gastroesophageal reflux disease (GERD), characterized by symptoms of heartburn and regurgitation, mild erosive esophagitis (Savary-Miller grade I-II), and objective evidence of pathologic acid reflux on 24-h pH monitoring [2]
.
- Efficacy Summary: Itopride at a dose of 100 mg three times daily for 4 weeks significantly improved both subjective symptoms (heartburn and total symptom scores) and objective measures of acid reflux (total time pH<4, percent time pH<4, DeMeester score) in patients with mild GERD. The 50 mg three times daily dose improved symptoms but had a more limited effect on pH-metry variables [2]
.
- Comparison with Other Prokinetics: Based on this study, itopride 300 mg/day appears to have similar efficacy in reducing acid reflux as other prokinetics like cisapride and mosapride, although direct comparative studies are needed. Its dual mechanism and favorable safety profile (lack of cardiac arrhythmia risk associated with cisapride) make it a potentially useful alternative [2]
.
- Dosage and Administration: In this study, itopride was administered orally at doses of 50 mg or 100 mg three times daily for 30 days [2]
.
- Safety Profile Relative to Other Prokinetics: Unlike some dopamine antagonists, itopride at standard doses (150 mg/day) does not commonly cause extrapyramidal symptoms or significant hyperprolactinemia. This may be due to its dual mechanism or its inability to readily cross the blood-brain barrier [2]
.
- Study Limitations: This was a pilot study with an open-label design and a relatively small sample size. Further double-blind, placebo-controlled studies with larger patient populations are needed to confirm these findings [2]
.

C20H27CLN2O4

394.89

394.165

122892-31-3

Itopride;122898-67-3;Itopride-d6 hydrochloride;1346601-02-2

129791

White to off-white solid powder

510.1ºC at 760 mmHg

194-1950ºC

262.3ºC

1.6E-10mmHg at 25°C

3.767

2

5

9

27

411

0

ZTOUXLLIPWWHSR-UHFFFAOYSA-N

InChI=1S/C20H26N2O4.ClH/c1-22(2)11-12-26-17-8-5-15(6-9-17)14-21-20(23)16-7-10-18(24-3)19(13-16)25-4;/h5-10,13H,11-12,14H2,1-4H3,(H,21,23);1H

N-[[4-[2-(dimethylamino)ethoxy]phenyl]methyl]-3,4-dimethoxybenzamide;hydrochloride

N-((4-(2-(Dimethylamino)ethoxy)phenyl)methyl)-3,4-dimethoxybenzamide monohydrochlorideItopride hydrochlorideHSR803 HSR-803HSR 803

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

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

DMSO : ~100 mg/mL (~253.24 mM)
H2O : ~50 mg/mL (~126.62 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (6.33 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (6.33 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
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.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (6.33 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 100 mg/mL (253.24 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

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