View source for Itopride

{{Short description|Chemical compound}}
{{Use dmy dates|date=October 2024}}
{{cs1 config |name-list-style=vanc |display-authors=6}}
{{Drugbox
| Verifiedfields = changed
| verifiedrevid = 444538072
| image = Itopride.svg
| width = 260
| alt =
| image2 = 3D Itopride.png
| alt2 =
<!--Clinical data-->
| tradename = Ganaton
| Drugs.com = {{drugs.com|international|itopride}}
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
| pregnancy_category =
| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled-->
| legal_CA = <!-- Schedule I, II, III, IV, V, VI, VII, VIII -->
| legal_UK = <!-- GSL, P, POM, CD, or Class A, B, C -->
| legal_US = <!-- OTC / Rx-only / Schedule I, II, III, IV, V -->
| legal_status = Rx-only
| routes_of_administration = [[Oral administration|By mouth]]
| ATC_prefix = A03
| ATC_suffix = FA07
| ATC_supplemental =
<!--Pharmacokinetic data-->
| bioavailability = ~60% ([[Cmax (pharmacology)|T<sub>max</sub>]] = 35±5 min)
| protein_bound = 96%
| metabolism = Extensive hepatic ([[Flavin containing monooxygenase 1|FMO1]] and [[Flavin containing monooxygenase 3|FMO3]]), primarily ''N''-oxidation<ref>{{cite book| veditors = Smith DA, Allerton C, Kubinyi H, van de Waterbeemd H, Walker DK |title=Pharmacokinetics and Metabolism in Drug Design|date=April 2012|publisher=Wiley-VCH|location=Weinheim|isbn=978-3-527-32954-0|page=132|edition=3rd}}</ref>
| elimination_half-life = 5.7±0.3 hours
| excretion = [[Kidney|Renal]] (3.7–4.1% as unchanged itopride, 75.4–89.4% as itopride-''N''-oxide)<ref>{{cite web|title=Ganaton (itopride hydrochloride) Tablets 50 mg. Prescribing Information|url=http://www.e-search.ne.jp/~jpr/PDF/ABBOTT00.PDF|publisher=Abbott Japan Co., Ltd.|access-date=9 December 2015|archive-url=https://web.archive.org/web/20151211011625/http://www.e-search.ne.jp/~jpr/PDF/ABBOTT00.PDF|archive-date=11 December 2015|url-status=dead}}</ref>
<!--Identifiers-->
| index2_label = as HCl
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 122898-67-3
| CAS_number2 = 122892-31-3
| PubChem = 3792
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB04924
| DrugBank2 = DBSALT002665
| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}
| ChemSpiderID = 3660
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 81BMQ80QRL
| UNII2 = 2H9NV66W0I
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D08094
| KEGG2 = D02729
| ChEBI = 94809
| ChEMBL = 2107457
<!--Chemical data-->
| IUPAC_name = ''N''-[<nowiki />[4-(2-Dimethylaminoethoxy)phenyl]methyl]-3,4-dimethoxybenzamide
| C=20 | H=26 | N=2 | O=4
| SMILES = CN(C)CCOC1=CC=C(C=C1)CNC(=O)C2=CC(=C(C=C2)OC)OC
| SMILES2 = Cl.COC1=CC=C(C=C1OC)C(=O)NCC1=CC=C(OCCN(C)C)C=C1
| StdInChI_Ref = {{stdinchicite|changed|chemspider}}
| StdInChI = 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)
| StdInChI2 = 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
| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}
| StdInChIKey = QQQIECGTIMUVDS-UHFFFAOYSA-N
| StdInChIKey2 = ZTOUXLLIPWWHSR-UHFFFAOYSA-N-UHFFFAOYSA-N
}}
'''Itopride''' ([[International Nonproprietary Name|INN]]; brand name '''Ganaton''') is a [[prokinetic]] [[benzamide]] derivative. These drugs inhibit [[dopamine]] and acetylcholine esterase enzyme and have a [[gastrokinetic]] effect.<ref name="pmid8835639">{{cite journal | vauthors = Iwanaga Y, Miyashita N, Saito T, Morikawa K, Itoh Z | title = Gastroprokinetic effect of a new benzamide derivative itopride and its action mechanisms in conscious dogs | journal = Japanese Journal of Pharmacology | volume = 71 | issue = 2 | pages = 129–137 | date = June 1996 | pmid = 8835639 | doi = 10.1254/jjp.71.129 | doi-access = free }}</ref> Itopride is indicated for the treatment of [[functional dyspepsia]] and other gastrointestinal conditions.<ref name="pmid16495395">{{cite journal | vauthors = Holtmann G, Talley NJ, Liebregts T, Adam B, Parow C | title = A placebo-controlled trial of itopride in functional dyspepsia | journal = The New England Journal of Medicine | volume = 354 | issue = 8 | pages = 832–840 | date = February 2006 | pmid = 16495395 | doi = 10.1056/NEJMoa052639 | doi-access = free }}</ref> It is a combined [[D2 receptor|D<sub>2</sub> receptor]] [[receptor antagonist|antagonist]] and [[acetylcholinesterase inhibitor]].<ref name="ParkmanMcCallum2011" /><ref name="CheyChey2011" /> [[Itopride]] is the dimethoxy analog of [[trimethobenzamide]].
==Medical uses==
[[Image:Ganaton2a.jpg|thumb|240px|A blister package of Ganaton (Itopride) 50&nbsp;mg tablets intended for distribution in the [[Slovak Republic]].]]
Typically, itopride is indicated in the treatment of GI symptoms caused by reduced GI motility:
*[[dyspepsia]] of a non-ulcer/dysmotility type (gastric "fullness", discomfort, and possible pain)<ref name="Huang-2012"/><ref name="Chiba-2007">{{cite journal | vauthors = Chiba T, Tokunaga Y, Ikeda K, Takagi R, Chishima R, Terui T, Kudara N, Endo M, Inomata M, Orii S, Suzuki K | display-authors = 6 | title = Effects of itopride hydrochloride and ranitidine in patients with functional dyspepsia: comparison between prokinetic and acid suppression therapies | journal = Hepato-Gastroenterology | volume = 54 | issue = 78 | pages = 1878–1881 | date = September 2007 | pmid = 18019739 }}</ref>
*[[Gastroparesis|gastroparesis (delayed gastric emptying)]]<ref name="Keil-2004">{{cite journal | vauthors = Keil R | title = [Prokinetics and diabetes mellitus] | journal = Vnitrni Lekarstvi | volume = 50 | issue = 5 | pages = 358, 360-358, 362 | date = May 2004 | pmid = 15305632 }}</ref><ref name="Kojecky 2005">{{Cite journal | vauthors = Kojecky V, Bernatek J, Bakala J, Weissova D |title = [The influence of itopride on the rate and course of the evacuation of stomach of the diabetic patients and their relationship to diabetes control] | journal = Ces.Slov.Gastroent.Hepatol., 2005 | volume = 59 | issue = 1 | pages = 17–20 |date= 2005 }}</ref>
*[[anorexia (symptom)|anorexia]]
*[[heartburn]]
*regurgitation
*bloating
*nausea and vomiting
*other possible gastric, prolactin, or dopamine related conditions
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.<ref>{{cite journal | vauthors = Holtmann G, Talley NJ, Liebregts T, Adam B, Parow C | title = A placebo-controlled trial of itopride in functional dyspepsia | journal = The New England Journal of Medicine | volume = 354 | issue = 8 | pages = 832–840 | date = February 2006 | pmid = 16495395 | doi = 10.1056/NEJMoa052639 | doi-access = free }}</ref>
== 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.<ref name="Huang-2012"/> Raising of prolactin levels is more common with high dose regimes of itopride.<ref name="Kim-2005">{{cite journal | vauthors = Kim YS, Kim TH, Choi CS, Shon YW, Kim SW, Seo GS, Nah YH, Choi MG, Choi SC | display-authors = 6 | title = Effect of itopride, a new prokinetic, in patients with mild GERD: a pilot study | journal = World Journal of Gastroenterology | volume = 11 | issue = 27 | pages = 4210–4214 | date = July 2005 | pmid = 16015691 | pmc = 4615444 | doi = 10.3748/wjg.v11.i27.4210 | doi-access = free }}</ref>
===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.<ref name="Huang-2012"/>
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 receptor|5-HT<sub>4</sub>]] receptors, unlike other [[benzamides]] such as cisapride and mosapride, which are 5-HT<sub>4</sub> agonists. The affinity of cisapride for 5-HT<sub>4</sub> receptors in the heart has been implicated in the undesirable cardiac effects of cisapride itself.{{medcn|date=December 2021}}
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.<ref>{{cite journal | vauthors = Gupta S, Kapoor V, Gupta BM, Verma U |year=2005 |title=Effect Of Itopride hydrochloride on QT interval in adult healthy volunteers |journal=JK-Practitioner |volume=12|issue=4 |pages=207–10 |url=http://medind.nic.in/jab/t05/i4/jabt05i4p207.pdf}}</ref>
==Pharmacology==
Itopride acts as a selective dual [[D2 receptor|D<sub>2</sub> receptor]] [[receptor antagonist|antagonist]] and [[acetylcholinesterase inhibitor]].<ref name="ParkmanMcCallum2011">{{cite book| vauthors = Parkman HP, McCallum RW |title=Gastroparesis: Pathophysiology, Presentation and Treatment|url=https://books.google.com/books?id=E2t1VL8wEzYC&pg=PA264|date=5 October 2011|publisher=Springer|isbn=978-1-60761-552-1|pages=264–}}</ref><ref name="CheyChey2011">{{cite book| vauthors = Chey WY, Chey WD |title=Irritable Bowel Syndrome, an Issue of Gastroenterology Clinics|url=https://books.google.com/books?id=YybJ8LdHIYsC&pg=PA232|year=2011|publisher=Elsevier Health Sciences|isbn=978-1-4557-0450-7|pages=232–}}</ref>
There is evidence that itopride may have prokinetic effects throughout the gastrointestinal tract from the stomach to the end of the colon.<ref name="Lim-2008">{{cite journal | vauthors = Lim HC, Kim YG, Lim JH, Kim HS, Park H | title = Effect of itopride hydrochloride on the ileal and colonic motility in guinea pig in vitro | journal = Yonsei Medical Journal | volume = 49 | issue = 3 | pages = 472–478 | date = June 2008 | pmid = 18581598 | pmc = 2615341 | doi = 10.3349/ymj.2008.49.3.472 }}</ref> 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.<ref name="Stevens-2008">{{cite journal | vauthors = Stevens JE, Russo A, Maddox AF, Rayner CK, Phillips L, Talley NJ, Giguère M, Horowitz M, Jones KL | display-authors = 6 | title = Effect of itopride on gastric emptying in longstanding diabetes mellitus | journal = Neurogastroenterology and Motility | volume = 20 | issue = 5 | pages = 456–463 | date = May 2008 | pmid = 18179609 | doi = 10.1111/j.1365-2982.2007.01058.x | s2cid = 25760696 }}</ref> 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.<ref name="Huang-2012">{{cite journal | vauthors = Huang X, Lv B, Zhang S, Fan YH, Meng LN | title = Itopride therapy for functional dyspepsia: a meta-analysis | journal = World Journal of Gastroenterology | volume = 18 | issue = 48 | pages = 7371–7377 | date = December 2012 | pmid = 23326147 | pmc = 3544044 | doi = 10.3748/wjg.v18.i48.7371 | doi-access = free }}</ref> Itopride has no effect on [[potassium channels]].<ref name="Morisawa-1999">{{cite journal | vauthors = Morisawa T, Hasegawa J, Hama R, Kitano M, Kishimoto Y, Kawasaki H | title = Effects of itopride hydrochloride on the delayed rectifier K+ and L-type CA2+ currents in guinea-pig ventricular myocytes | journal = Research Communications in Molecular Pathology and Pharmacology | volume = 106 | issue = 1–2 | pages = 37–45 | year = 1999 | pmid = 11127807 }}</ref>
Similarly to other D<sub>2</sub> receptor antagonists, itopride has been found to dose-dependently increase [[prolactin]] levels.<ref name="CheyChey2011" />
===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.<ref name="Bose-2013">{{cite journal | vauthors = Bose A, Wong TW, Singh N | title = Formulation development and optimization of sustained release matrix tablet of Itopride HCl by response surface methodology and its evaluation of release kinetics | journal = Saudi Pharmaceutical Journal | volume = 21 | issue = 2 | pages = 201–213 | date = April 2013 | pmid = 23960836 | pmc = 3744972 | doi = 10.1016/j.jsps.2012.03.006 }}</ref>
===Mechanism of action===
[[Image:Ganaton1.jpg|thumb|Ganaton (Itopride) 50&nbsp;mg tablets. Engraving says "HC 803"]]
Itopride increases [[acetylcholine]] concentrations by inhibiting [[Dopamine receptor D2|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.<ref name="Huang-2012"/>
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.<ref name="Katagiri-2006">{{cite journal | vauthors = Katagiri F, Shiga T, Inoue S, Sato Y, Itoh H, Takeyama M | title = Effects of itopride hydrochloride on plasma gut-regulatory peptide and stress-related hormone levels in healthy human subjects | journal = Pharmacology | volume = 77 | issue = 3 | pages = 115–121 | year = 2006 | pmid = 16717477 | doi = 10.1159/000093485 | s2cid = 22219251 }}</ref>
== 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 <ref>{{Cite web|url=http://www.bda.bg/images/stories/documents/bdias/Z-1.htm|title = Z}}</ref>
== References ==
{{reflist}}
== External links ==
* {{ClinicalTrialsGov|NCT00272103|Itopride in Functional Dyspepsia:a Dose Finding Study}}
{{Drugs for functional gastrointestinal disorders}}
{{Acetylcholine metabolism and transport modulators}}
{{Dopamine receptor modulators}}
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[[Category:Acetylcholinesterase inhibitors]]
[[Category:Benzamides]]
[[Category:D2 antagonists]]
[[Category:Drugs developed by AbbVie]]
[[Category:Drugs developed by Takeda Pharmaceutical Company]]
[[Category:Motility stimulants]]
[[Category:Catechol ethers]]
[[Category:Peripherally selective drugs]]
[[de:Prokinetikum]]
[[es:Procinético]]
[[ja:イトプリド塩酸塩]]
[[pl:Leki prokinetyczne]]