Itopride

Itopride
Clinical data
Trade namesGanaton
AHFS/Drugs.comInternational Drug Names
Routes of
administration		By mouth
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability~60% (Tmax = 35±5 min)
Protein binding96%
MetabolismExtensive hepatic (FMO1 and FMO3), primarily N-oxidation[2]
Elimination half-life5.7±0.3 hours
ExcretionRenal (3.7–4.1% as unchanged itopride, 75.4–89.4% as itopride-N-oxide)[1]
Identifiers
  • N-[[4-(2-Dimethylaminoethoxy)phenyl]methyl]-3,4-dimethoxybenzamide
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.222.888 Edit this at Wikidata
Chemical and physical data
FormulaC20H26N2O4
Molar mass358.438 g·mol−1
3D model (JSmol)
  • CN(C)CCOC1=CC=C(C=C1)CNC(=O)C2=CC(=C(C=C2)OC)OC

  • as HCl: Cl.COC1=CC=C(C=C1OC)C(=O)NCC1=CC=C(OCCN(C)C)C=C1
  • InChI=1S/C20H26N2O4/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) ☒N
  • Key:QQQIECGTIMUVDS-UHFFFAOYSA-N ☒N

  • as HCl: 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
  • Key:ZTOUXLLIPWWHSR-UHFFFAOYSA-N-UHFFFAOYSA-N
 ☒NcheckY (what is this?)  (verify)

Itopride (INN; brand name Ganaton) is a prokinetic benzamide derivative. These drugs inhibit dopamine and acetylcholine esterase enzyme and have a gastrokinetic effect.[3] Itopride is indicated for the treatment of functional dyspepsia and other gastrointestinal conditions.[4] It is a combined D2 receptor antagonist and acetylcholinesterase inhibitor.[5][6] Itopride is the dimethoxy analog of trimethobenzamide.

Medical uses

A blister package of Ganaton (Itopride) 50 mg tablets intended for distribution in the Slovak Republic.

Typically, itopride is indicated in the treatment of GI symptoms caused by reduced GI motility:

Itopride was shown to significantly improve symptoms in patients with functional dyspepsia and motility disorders in placebo-controlled trials.

These studies concluded that the reduction in the severity of symptoms of functional dyspepsia after 8 weeks of treatment with itopride indicated that itopride was significantly superior to placebo and that itopride yielded a greater rate of response than placebo in significantly reducing pain and fullness.[4]

Adverse drug reactions

Central nervous system adverse effects do not tend to occur due to poor penetration across the blood brain barrier, although a slight raising of prolactin levels may occur.[7] Raising of prolactin levels is more common with high dose regimes of itopride.[11]

Cardiac studies

Itopride belongs to the same benzamide group as cisapride, a drug found to affect QT interval and possibly predispose those using it to cardiac arrhythmias. However, itopride does not have any adverse effect on the QT interval.[7]

Later, in a study conducted with healthy adult volunteers, itopride was shown as unlikely to cause cardiac arrhythmias or ECG changes in part to the lack of significant interaction and metabolism via the cytochrome P450 enzyme pathway, unlike cisapride and mosapride, as it is metabolized by a different enzyme set. New molecular studies on guinea pig ventricular myocytes also supported the cardiac safety profile of itopride, as it did not affect certain potassium mechanisms that may have been affected by cisapride or mosapride. Moreover, itopride has no affinity for the 5-HT4 receptors, unlike other benzamides such as cisapride and mosapride, which are 5-HT4 agonists. The affinity of cisapride for 5-HT4 receptors in the heart has been implicated in the undesirable cardiac effects of cisapride itself.[medical citation needed]

The conclusion of this study revealed that itopride is devoid of any abnormal effect on QT interval. Therefore, it may be possible that itopride could be considered as a better and certainly safer prokinetic agent than either cisapride or mosapride, and itopride should also be considered a welcome treatment addition for symptomatic nonulcer dyspepsia and other gastric motility disorders.[12]

Pharmacology

Itopride acts as a selective dual D2 receptor antagonist and acetylcholinesterase inhibitor.[5][6]

There is evidence that itopride may have prokinetic effects throughout the gastrointestinal tract from the stomach to the end of the colon.[13] The pharmacokinetics of itopride appear to differ between Asian and Caucasian populations, with Caucasians having 30-50 percent lower blood levels of itopride after oral administration.[14] Itopride poorly penetrates across the blood brain barrier because of its high polarity and thus itopride does not tend to cause any central nervous system adverse effects.[7] Itopride has no effect on potassium channels.[15]

Similarly to other D2 receptor antagonists, itopride has been found to dose-dependently increase prolactin levels.[6]

Pharmacokinetics

After oral administration itopride undergoes rapid and extensive absorption with levels of itopride peaking in the blood plasma after only 35 minutes. Itopride is primarily eliminated via the kidneys having an elimination half-life of approximately 6 hours.[16]

Mechanism of action

Ganaton (Itopride) 50 mg tablets. Engraving says "HC 803"

Itopride increases acetylcholine concentrations by inhibiting dopamine D2 receptors and acetylcholinesterase. Higher acetylcholine increases GI peristalsis, increases the lower esophageal sphincter pressure, stimulates gastric motility, accelerates gastric emptying, and improves gastro-duodenal coordination.[7]

Itopride given as a single dose study found that it also raises levels of motilin, somatostatin and lowers levels of cholecystokinin, as well as adrenocorticotropic hormone. These effects may also contribute to itopride's pharmacology.[17]

Society and culture

Names

Itopride is available under various brand names including Ganaton (Japan, Czech Republic, Russian Federation), Itoprid PMCS (Czech Republic, Slovakia), Itomed (Kyrgyzstan, Kazakhstan, Moldova, Russia, Ukraine, Uzbekistan), Prokit (Poland), and Itogard (Nepal). In Mexico, itopride is sold by Takeda Laboratories under the brand name Dagla. In Bulgaria and other countries of East Europe itopride is sold by Zentiva under the brand name Zirid [18]

References

  1. ^ "Ganaton (itopride hydrochloride) Tablets 50 mg. Prescribing Information" (PDF). Abbott Japan Co., Ltd. Archived from the original (PDF) on 11 December 2015. Retrieved 9 December 2015.
  2. ^ Smith DA, Allerton C, Kubinyi H, van de Waterbeemd H, Walker DK, eds. (April 2012). Pharmacokinetics and Metabolism in Drug Design (3rd ed.). Weinheim: Wiley-VCH. p. 132. ISBN 978-3-527-32954-0.
  3. ^ Iwanaga Y, Miyashita N, Saito T, Morikawa K, Itoh Z (June 1996). "Gastroprokinetic effect of a new benzamide derivative itopride and its action mechanisms in conscious dogs". Japanese Journal of Pharmacology. 71 (2): 129–137. doi:10.1254/jjp.71.129. PMID 8835639.
  4. ^ a b Holtmann G, Talley NJ, Liebregts T, Adam B, Parow C (February 2006). "A placebo-controlled trial of itopride in functional dyspepsia". The New England Journal of Medicine. 354 (8): 832–840. doi:10.1056/NEJMoa052639. PMID 16495395.
  5. ^ a b Parkman HP, McCallum RW (5 October 2011). Gastroparesis: Pathophysiology, Presentation and Treatment. Springer. pp. 264–. ISBN 978-1-60761-552-1.
  6. ^ a b c Chey WY, Chey WD (2011). Irritable Bowel Syndrome, an Issue of Gastroenterology Clinics. Elsevier Health Sciences. pp. 232–. ISBN 978-1-4557-0450-7.
  7. ^ a b c d e Huang X, Lv B, Zhang S, Fan YH, Meng LN (December 2012). "Itopride therapy for functional dyspepsia: a meta-analysis". World Journal of Gastroenterology. 18 (48): 7371–7377. doi:10.3748/wjg.v18.i48.7371. PMC 3544044. PMID 23326147.
  8. ^ Chiba T, Tokunaga Y, Ikeda K, Takagi R, Chishima R, Terui T, et al. (September 2007). "Effects of itopride hydrochloride and ranitidine in patients with functional dyspepsia: comparison between prokinetic and acid suppression therapies". Hepato-Gastroenterology. 54 (78): 1878–1881. PMID 18019739.{{cite journal}}: CS1 maint: overridden setting (link)
  9. ^ Keil R (May 2004). "[Prokinetics and diabetes mellitus]". Vnitrni Lekarstvi. 50 (5): 358, 360–358, 362. PMID 15305632.
  10. ^ Kojecky V, Bernatek J, Bakala J, Weissova D (2005). "[The influence of itopride on the rate and course of the evacuation of stomach of the diabetic patients and their relationship to diabetes control]". Ces.Slov.Gastroent.Hepatol., 2005. 59 (1): 17–20.
  11. ^ Kim YS, Kim TH, Choi CS, Shon YW, Kim SW, Seo GS, et al. (July 2005). "Effect of itopride, a new prokinetic, in patients with mild GERD: a pilot study". World Journal of Gastroenterology. 11 (27): 4210–4214. doi:10.3748/wjg.v11.i27.4210. PMC 4615444. PMID 16015691.{{cite journal}}: CS1 maint: overridden setting (link)
  12. ^ Gupta S, Kapoor V, Gupta BM, Verma U (2005). "Effect Of Itopride hydrochloride on QT interval in adult healthy volunteers" (PDF). JK-Practitioner. 12 (4): 207–10.
  13. ^ Lim HC, Kim YG, Lim JH, Kim HS, Park H (June 2008). "Effect of itopride hydrochloride on the ileal and colonic motility in guinea pig in vitro". Yonsei Medical Journal. 49 (3): 472–478. doi:10.3349/ymj.2008.49.3.472. PMC 2615341. PMID 18581598.
  14. ^ Stevens JE, Russo A, Maddox AF, Rayner CK, Phillips L, Talley NJ, et al. (May 2008). "Effect of itopride on gastric emptying in longstanding diabetes mellitus". Neurogastroenterology and Motility. 20 (5): 456–463. doi:10.1111/j.1365-2982.2007.01058.x. PMID 18179609. S2CID 25760696.{{cite journal}}: CS1 maint: overridden setting (link)
  15. ^ Morisawa T, Hasegawa J, Hama R, Kitano M, Kishimoto Y, Kawasaki H (1999). "Effects of itopride hydrochloride on the delayed rectifier K+ and L-type CA2+ currents in guinea-pig ventricular myocytes". Research Communications in Molecular Pathology and Pharmacology. 106 (1–2): 37–45. PMID 11127807.
  16. ^ Bose A, Wong TW, Singh N (April 2013). "Formulation development and optimization of sustained release matrix tablet of Itopride HCl by response surface methodology and its evaluation of release kinetics". Saudi Pharmaceutical Journal. 21 (2): 201–213. doi:10.1016/j.jsps.2012.03.006. PMC 3744972. PMID 23960836.
  17. ^ Katagiri F, Shiga T, Inoue S, Sato Y, Itoh H, Takeyama M (2006). "Effects of itopride hydrochloride on plasma gut-regulatory peptide and stress-related hormone levels in healthy human subjects". Pharmacology. 77 (3): 115–121. doi:10.1159/000093485. PMID 16717477. S2CID 22219251.
  18. ^ "Z".