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Details

Stereochemistry ACHIRAL
Molecular Formula C28H28N2O2.ClH
Molecular Weight 460.995
Optical Activity NONE
Defined Stereocenters 0 / 0
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of DIFENOXIN HYDROCHLORIDE

SMILES

Cl.OC(=O)C1(CCN(CCC(C#N)(C2=CC=CC=C2)C3=CC=CC=C3)CC1)C4=CC=CC=C4

InChI

InChIKey=VMIZTXDGZPTKIK-UHFFFAOYSA-N
InChI=1S/C28H28N2O2.ClH/c29-22-28(24-12-6-2-7-13-24,25-14-8-3-9-15-25)18-21-30-19-16-27(17-20-30,26(31)32)23-10-4-1-5-11-23;/h1-15H,16-21H2,(H,31,32);1H

HIDE SMILES / InChI
Difenoxin is a 4-phenylpiperidine which is closely related to the opioid analgesic meperidine. Difenoxin alone is a USA Schedule I controlled drug, as it may be habit forming. However, it is listed as a Schedule IV controlled drug if combined with atropine, which is added to decrease deliberate misuse. Motofen(R) is a brand mixture which combines atropine sulfate and difenoxin hydrochloride. It is approved by the FDA to treat acute and chronic diarrhea. Difenoxin is an active metabolite of the anti-diarrheal drug, diphenoxylate, which is also used in combination with atropine in the brand mixture Lomotil(R). It works mostly in the periphery and activates opioid receptors in the intestine rather than the central nervous system (CNS). Difenoxin is also closely related to loperamide, but unlike loperamide it is still capable of crossing the blood brain barrier to produce weak sedative and analgesic effects. However, the antidiarrheal potency of difenoxin is much greater than its CNS effects, which makes it an attractive alternative to other opioids. Motofen(R) is a combination of atropine, an anticholinergic drug, and difenoxin, an antidiarrheal drug. It has been used in many countries for many years as a second line opioid-agonist antidiarrheal, which exists an intermediate between loperamide and paragoric. Diarrhea which is a result of cyclic or diarrhea predominant Inflammatory Bowel Syndrome may not be treated effectively with difenoxin, diphenoxylate, or loperamide. As such, diarrhea and cramping which does not respond to non-centrally acting derivatives or belladonna derivatives such as atropine are often treated with conservative doses of codeine. In patients with acute ulcerative colitis, as induction of toxic megacolon is possible, and thus use of Motofen(R) is cautioned. Motofen(R) has been assigned pregnancy category C by the FDA, and is to be used only when the potential benefits outweigh the potential risk to the fetus. The safety of use during lactation is unknown and thus not recommended. Each five-sided dye free MOTOFEN® tablet contains: 1 mg of difenoxin (equivalent to 1.09 mg of difenoxin hydrochloride) and 0.025 mg of atropine sulfate (equivalent to 0.01 mg of atropine). Difenoxin acts as an antidiarrheal by activating peripheral opioid receptors in the small intestine and thereby inhibiting peristalsis. However, research has suggested that non-opioid receptor pathways exist. This would explain the potent antidiarrheal effects of difenoxin despite only limited opioid action.

CNS Activity

Curator's Comment: Difenoxin crosses the blood–brain barrier and can cause mild euphoria, difenoxin in high doses can produce adverse CNS effects.

Approval Year

TargetsConditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
MOTOFEN

Approved Use

MOTOFEN® is indicated as adjunctive therapy in the management of acute nonspecific diarrhea and acute exacerbations of chronic functional diarrhea.

Launch Date

2.69222396E11
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
160 ng/mL
1 mg single, oral
dose: 1 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
DIFENOXIN plasma
Homo sapiens
population: UNKNOWN
age: ADULT
sex: UNKNOWN
food status: UNKNOWN
Doses

Doses

DosePopulationAdverse events​
2 mg multiple, oral (starting)
Dose: 2 mg
Route: oral
Route: multiple
Dose: 2 mg
Co-administed with::
atropine sulfate(2 tablets)
Sources:
unhealthy, adult
n = 100
Health Status: unhealthy
Condition: acute nonspecific diarrhea
Age Group: adult
Population Size: 100
Sources:
Other AEs: Epigastric distress...
Other AEs:
Epigastric distress (1 patient)
Sources:
2 mg multiple, oral (starting)
Dose: 2 mg
Route: oral
Route: multiple
Dose: 2 mg
Co-administed with::
atropine sulfate(2 tablets)
Sources:
unhealthy, adult
n = 15
Health Status: unhealthy
Condition: acute nonspecific diarrhea
Age Group: adult
Population Size: 15
Sources:
Other AEs: Nausea...
2 mg multiple, oral (starting)
Dose: 2 mg
Route: oral
Route: multiple
Dose: 2 mg
Co-administed with::
atropine sulfate(2 tablets)
Sources:
unhealthy, adult
n = 20
Health Status: unhealthy
Condition: acute nonspecific diarrhea
Age Group: adult
Population Size: 20
Sources:
Other AEs: Constipation, Dizziness...
Other AEs:
Constipation (1 patient)
Dizziness (1 patient)
Sources:
2 mg multiple, oral (starting)
Dose: 2 mg
Route: oral
Route: multiple
Dose: 2 mg
Co-administed with::
atropine sulfate(2 tablets)
Sources:
unhealthy, adult
n = 25
Health Status: unhealthy
Condition: acute nonspecific diarrhea
Age Group: adult
Population Size: 25
Sources:
Other AEs: Light headedness...
2 mg multiple, oral (starting)
Dose: 2 mg
Route: oral
Route: multiple
Dose: 2 mg
Co-administed with::
atropine sulfate(2 tablets)
Sources:
unhealthy, adult
n = 30
Health Status: unhealthy
Condition: acute nonspecific diarrhea
Age Group: adult
Population Size: 30
Sources:
Other AEs: Vomiting, Dry mouth...
Other AEs:
Vomiting (1 patient)
Dry mouth (1 patient)
Sources:
2 mg multiple, oral (starting)
Dose: 2 mg
Route: oral
Route: multiple
Dose: 2 mg
Co-administed with::
atropine sulfate(2 tablets)
Sources:
unhealthy, adult
n = 40
Health Status: unhealthy
Condition: acute nonspecific diarrhea
Age Group: adult
Population Size: 40
Sources:
Other AEs: Drowsiness, Headache...
Other AEs:
Drowsiness (1 patient)
Headache (1 patient)
Sources:
AEs

AEs

AESignificanceDosePopulation
Epigastric distress 1 patient
2 mg multiple, oral (starting)
Dose: 2 mg
Route: oral
Route: multiple
Dose: 2 mg
Co-administed with::
atropine sulfate(2 tablets)
Sources:
unhealthy, adult
n = 100
Health Status: unhealthy
Condition: acute nonspecific diarrhea
Age Group: adult
Population Size: 100
Sources:
Nausea 1 patient
2 mg multiple, oral (starting)
Dose: 2 mg
Route: oral
Route: multiple
Dose: 2 mg
Co-administed with::
atropine sulfate(2 tablets)
Sources:
unhealthy, adult
n = 15
Health Status: unhealthy
Condition: acute nonspecific diarrhea
Age Group: adult
Population Size: 15
Sources:
Constipation 1 patient
2 mg multiple, oral (starting)
Dose: 2 mg
Route: oral
Route: multiple
Dose: 2 mg
Co-administed with::
atropine sulfate(2 tablets)
Sources:
unhealthy, adult
n = 20
Health Status: unhealthy
Condition: acute nonspecific diarrhea
Age Group: adult
Population Size: 20
Sources:
Dizziness 1 patient
2 mg multiple, oral (starting)
Dose: 2 mg
Route: oral
Route: multiple
Dose: 2 mg
Co-administed with::
atropine sulfate(2 tablets)
Sources:
unhealthy, adult
n = 20
Health Status: unhealthy
Condition: acute nonspecific diarrhea
Age Group: adult
Population Size: 20
Sources:
Light headedness 1 patient
2 mg multiple, oral (starting)
Dose: 2 mg
Route: oral
Route: multiple
Dose: 2 mg
Co-administed with::
atropine sulfate(2 tablets)
Sources:
unhealthy, adult
n = 25
Health Status: unhealthy
Condition: acute nonspecific diarrhea
Age Group: adult
Population Size: 25
Sources:
Dry mouth 1 patient
2 mg multiple, oral (starting)
Dose: 2 mg
Route: oral
Route: multiple
Dose: 2 mg
Co-administed with::
atropine sulfate(2 tablets)
Sources:
unhealthy, adult
n = 30
Health Status: unhealthy
Condition: acute nonspecific diarrhea
Age Group: adult
Population Size: 30
Sources:
Vomiting 1 patient
2 mg multiple, oral (starting)
Dose: 2 mg
Route: oral
Route: multiple
Dose: 2 mg
Co-administed with::
atropine sulfate(2 tablets)
Sources:
unhealthy, adult
n = 30
Health Status: unhealthy
Condition: acute nonspecific diarrhea
Age Group: adult
Population Size: 30
Sources:
Drowsiness 1 patient
2 mg multiple, oral (starting)
Dose: 2 mg
Route: oral
Route: multiple
Dose: 2 mg
Co-administed with::
atropine sulfate(2 tablets)
Sources:
unhealthy, adult
n = 40
Health Status: unhealthy
Condition: acute nonspecific diarrhea
Age Group: adult
Population Size: 40
Sources:
Headache 1 patient
2 mg multiple, oral (starting)
Dose: 2 mg
Route: oral
Route: multiple
Dose: 2 mg
Co-administed with::
atropine sulfate(2 tablets)
Sources:
unhealthy, adult
n = 40
Health Status: unhealthy
Condition: acute nonspecific diarrhea
Age Group: adult
Population Size: 40
Sources:
Overview

Overview

CYP3A4CYP2C9CYP2D6hERG

OverviewOther

Other InhibitorOther SubstrateOther Inducer

Drug as perpetrator​

Drug as perpetrator​

TargetModalityActivityMetaboliteClinical evidence
likely
PubMed

PubMed

TitleDatePubMed
Medical management of fecal incontinence.
2004 Jan
Bowel management for the treatment of pediatric fecal incontinence.
2009 Dec
Patents

Patents

Sample Use Guides

Each five-sided dye free MOTOFEN® tablet contains: 1 mg of difenoxin (equivalent to 1.09 mg of difenoxin hydrochloride) and 0.025 mg of atropine sulfate (equivalent to 0.01 mg of atropine). The recommended starting dose of MOTOFEN® tablets in adults is 2 tablets then 1 tablet after each loose stool or 1 tablet every 3 to 4 hours as needed, but the total dosage during any 24-hour treatment period should not exceed 8 tablets. In the treatment of diarrhea, if clinical improvement is not observed in 48 hours, continued administration of this type of medication is not recommended. For acute diarrheas and acute exacerbations of functional diarrhea, treatment beyond 48 hours is usually not necessary.
Route of Administration: Oral
In Vitro Use Guide
Difenoxin decreased the rate of peristalsis in the rat isolated ileum with IC=10.4 nM.
Name Type Language
DIFENOXIN HYDROCHLORIDE
MART.   ORANGE BOOK   VANDF   WHO-DD  
Common Name English
DIFENOXIN HYDROCHLORIDE [MART.]
Common Name English
R 15,403
Code English
Difenoxin hydrochloride [WHO-DD]
Common Name English
DIFENOXIN HYDROCHLORIDE [ORANGE BOOK]
Common Name English
DIFENOXIN HYDROCHLORIDE [VANDF]
Common Name English
DIFENOXINE HYDROCHLORIDE
Common Name English
4-PIPERIDINECARBOXYLIC ACID, 1-(3-CYANO-3,3-DIPHENYLPROPYL)-4-PHENYL-, HYDROCHLORIDE (1:1)
Systematic Name English
R-15403 (AS HYDROCHLORIDE)
Code English
MOTOFEN COMPONENT DIFENOXIN HYDROCHLORIDE
Common Name English
R-15403
Code English
DIFENOXIN HYDROCHLORIDE COMPONENT OF MOTOFEN
Common Name English
DIFENOXIN HCL
Common Name English
Classification Tree Code System Code
NCI_THESAURUS C266
Created by admin on Wed Jul 05 22:50:52 UTC 2023 , Edited by admin on Wed Jul 05 22:50:52 UTC 2023
Code System Code Type Description
DRUG BANK
DBSALT000047
Created by admin on Wed Jul 05 22:50:52 UTC 2023 , Edited by admin on Wed Jul 05 22:50:52 UTC 2023
PRIMARY
EPA CompTox
DTXSID30956985
Created by admin on Wed Jul 05 22:50:52 UTC 2023 , Edited by admin on Wed Jul 05 22:50:52 UTC 2023
PRIMARY
SMS_ID
100000087945
Created by admin on Wed Jul 05 22:50:52 UTC 2023 , Edited by admin on Wed Jul 05 22:50:52 UTC 2023
PRIMARY
ECHA (EC/EINECS)
252-640-7
Created by admin on Wed Jul 05 22:50:52 UTC 2023 , Edited by admin on Wed Jul 05 22:50:52 UTC 2023
PRIMARY
CHEBI
59790
Created by admin on Wed Jul 05 22:50:52 UTC 2023 , Edited by admin on Wed Jul 05 22:50:52 UTC 2023
PRIMARY
CAS
35607-36-4
Created by admin on Wed Jul 05 22:50:52 UTC 2023 , Edited by admin on Wed Jul 05 22:50:52 UTC 2023
PRIMARY
ChEMBL
CHEMBL1201321
Created by admin on Wed Jul 05 22:50:52 UTC 2023 , Edited by admin on Wed Jul 05 22:50:52 UTC 2023
PRIMARY
MESH
C100010
Created by admin on Wed Jul 05 22:50:52 UTC 2023 , Edited by admin on Wed Jul 05 22:50:52 UTC 2023
PRIMARY
FDA UNII
VQZ63K01IW
Created by admin on Wed Jul 05 22:50:52 UTC 2023 , Edited by admin on Wed Jul 05 22:50:52 UTC 2023
PRIMARY
NCI_THESAURUS
C47487
Created by admin on Wed Jul 05 22:50:52 UTC 2023 , Edited by admin on Wed Jul 05 22:50:52 UTC 2023
PRIMARY
DAILYMED
VQZ63K01IW
Created by admin on Wed Jul 05 22:50:52 UTC 2023 , Edited by admin on Wed Jul 05 22:50:52 UTC 2023
PRIMARY
PUBCHEM
37193
Created by admin on Wed Jul 05 22:50:52 UTC 2023 , Edited by admin on Wed Jul 05 22:50:52 UTC 2023
PRIMARY
EVMPD
SUB01691MIG
Created by admin on Wed Jul 05 22:50:52 UTC 2023 , Edited by admin on Wed Jul 05 22:50:52 UTC 2023
PRIMARY
RXCUI
235373
Created by admin on Wed Jul 05 22:50:52 UTC 2023 , Edited by admin on Wed Jul 05 22:50:52 UTC 2023
PRIMARY RxNorm
WIKIPEDIA
Difenoxin hydrochloride
Created by admin on Wed Jul 05 22:50:52 UTC 2023 , Edited by admin on Wed Jul 05 22:50:52 UTC 2023
PRIMARY