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Details

Stereochemistry ACHIRAL
Molecular Formula C28H28N2O2
Molecular Weight 424.5341
Optical Activity NONE
Defined Stereocenters 0 / 0
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of DIFENOXIN

SMILES

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

InChI

InChIKey=UFIVBRCCIRTJTN-UHFFFAOYSA-N
InChI=1S/C28H28N2O2/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)

HIDE SMILES / InChI

Molecular Formula C28H28N2O2
Molecular Weight 424.5341
Charge 0
Count
Stereochemistry ACHIRAL
Additional Stereochemistry No
Defined Stereocenters 0 / 0
E/Z Centers 0
Optical Activity NONE

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
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.
Substance Class Chemical
Created
by admin
on Fri Dec 15 15:59:39 UTC 2023
Edited
by admin
on Fri Dec 15 15:59:39 UTC 2023
Record UNII
3ZZ5BJ9F2Q
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
DIFENOXIN
INN   MART.   MI   USAN   VANDF   WHO-DD  
USAN   INN  
Official Name English
Difenoxin [WHO-DD]
Common Name English
DIPHENOXYLATE RELATED COMPOUND A [USP-RS]
Common Name English
1-(3-Cyano-3,3-diphenylpropyl)-4-phenylisonipecotic acid
Systematic Name English
R-15403 FREE BASE
Code English
4-PIPERIDINECARBOXYLIC ACID, 1-(3-CYANO-3,3-DIPHENYLPROPYL)-4-PHENYL-
Common Name English
MCN-JR 15403-11
Common Name English
DIFENOXIN [MART.]
Common Name English
DIFENOXIN [USAN]
Common Name English
IDS-ND-007
Code English
DIFENOXINE
Common Name English
ACSCN-9168
Common Name English
LYSPAFEN
Common Name English
DIFENOXIN [MI]
Common Name English
DIFENOXIN [VANDF]
Common Name English
difenoxin [INN]
Common Name English
DIPHENOXYLATE RELATED COMPOUND A CI
USP-RS  
Common Name English
R 15,403 FREE BASE
Code English
MCN-JR-15,403-11
Code English
DIPHENOXYLIC ACID
Common Name English
Classification Tree Code System Code
LIVERTOX 304
Created by admin on Fri Dec 15 15:59:39 UTC 2023 , Edited by admin on Fri Dec 15 15:59:39 UTC 2023
DEA NO. 9168
Created by admin on Fri Dec 15 15:59:39 UTC 2023 , Edited by admin on Fri Dec 15 15:59:39 UTC 2023
DEA NO. 9167
Created by admin on Fri Dec 15 15:59:39 UTC 2023 , Edited by admin on Fri Dec 15 15:59:39 UTC 2023
WHO-ATC A07DA04
Created by admin on Fri Dec 15 15:59:39 UTC 2023 , Edited by admin on Fri Dec 15 15:59:39 UTC 2023
WHO-VATC QA07DA04
Created by admin on Fri Dec 15 15:59:39 UTC 2023 , Edited by admin on Fri Dec 15 15:59:39 UTC 2023
NCI_THESAURUS C266
Created by admin on Fri Dec 15 15:59:39 UTC 2023 , Edited by admin on Fri Dec 15 15:59:39 UTC 2023
NDF-RT N0000178374
Created by admin on Fri Dec 15 15:59:39 UTC 2023 , Edited by admin on Fri Dec 15 15:59:39 UTC 2023
Code System Code Type Description
DAILYMED
3ZZ5BJ9F2Q
Created by admin on Fri Dec 15 15:59:39 UTC 2023 , Edited by admin on Fri Dec 15 15:59:39 UTC 2023
PRIMARY
EPA CompTox
DTXSID0022931
Created by admin on Fri Dec 15 15:59:39 UTC 2023 , Edited by admin on Fri Dec 15 15:59:39 UTC 2023
PRIMARY
CHEBI
4534
Created by admin on Fri Dec 15 15:59:39 UTC 2023 , Edited by admin on Fri Dec 15 15:59:39 UTC 2023
PRIMARY
IUPHAR
7592
Created by admin on Fri Dec 15 15:59:39 UTC 2023 , Edited by admin on Fri Dec 15 15:59:39 UTC 2023
PRIMARY
DRUG CENTRAL
878
Created by admin on Fri Dec 15 15:59:39 UTC 2023 , Edited by admin on Fri Dec 15 15:59:39 UTC 2023
PRIMARY
RS_ITEM_NUM
1219019
Created by admin on Fri Dec 15 15:59:39 UTC 2023 , Edited by admin on Fri Dec 15 15:59:39 UTC 2023
PRIMARY
SMS_ID
100000083174
Created by admin on Fri Dec 15 15:59:39 UTC 2023 , Edited by admin on Fri Dec 15 15:59:39 UTC 2023
PRIMARY
RXCUI
23024
Created by admin on Fri Dec 15 15:59:39 UTC 2023 , Edited by admin on Fri Dec 15 15:59:39 UTC 2023
PRIMARY RxNorm
MESH
C100010
Created by admin on Fri Dec 15 15:59:39 UTC 2023 , Edited by admin on Fri Dec 15 15:59:39 UTC 2023
PRIMARY
ChEMBL
CHEMBL1201321
Created by admin on Fri Dec 15 15:59:39 UTC 2023 , Edited by admin on Fri Dec 15 15:59:39 UTC 2023
PRIMARY
EVMPD
SUB07123MIG
Created by admin on Fri Dec 15 15:59:39 UTC 2023 , Edited by admin on Fri Dec 15 15:59:39 UTC 2023
PRIMARY
NCI_THESAURUS
C65381
Created by admin on Fri Dec 15 15:59:39 UTC 2023 , Edited by admin on Fri Dec 15 15:59:39 UTC 2023
PRIMARY
INN
2903
Created by admin on Fri Dec 15 15:59:39 UTC 2023 , Edited by admin on Fri Dec 15 15:59:39 UTC 2023
PRIMARY
DRUG BANK
DB01501
Created by admin on Fri Dec 15 15:59:39 UTC 2023 , Edited by admin on Fri Dec 15 15:59:39 UTC 2023
PRIMARY
PUBCHEM
34328
Created by admin on Fri Dec 15 15:59:39 UTC 2023 , Edited by admin on Fri Dec 15 15:59:39 UTC 2023
PRIMARY
FDA UNII
3ZZ5BJ9F2Q
Created by admin on Fri Dec 15 15:59:39 UTC 2023 , Edited by admin on Fri Dec 15 15:59:39 UTC 2023
PRIMARY
CAS
28782-42-5
Created by admin on Fri Dec 15 15:59:39 UTC 2023 , Edited by admin on Fri Dec 15 15:59:39 UTC 2023
PRIMARY
MERCK INDEX
m4425
Created by admin on Fri Dec 15 15:59:39 UTC 2023 , Edited by admin on Fri Dec 15 15:59:39 UTC 2023
PRIMARY Merck Index
WIKIPEDIA
DIFENOXIN
Created by admin on Fri Dec 15 15:59:39 UTC 2023 , Edited by admin on Fri Dec 15 15:59:39 UTC 2023
PRIMARY
Related Record Type Details
SALT/SOLVATE -> PARENT
APPROXIMATE PURE ANHYDROUS DRUG CONTENT (IN PERCENT)
Related Record Type Details
PARENT -> METABOLITE
Metabolite to parent drug ratio in non-uraemic human plasma.
URINE
PARENT -> METABOLITE
Percent of dose excreted in urine as metabolite.
URINE
Related Record Type Details
PARENT -> IMPURITY
CHROMATOGRAPHIC PURITY (HPLC/UV)
USP
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ACTIVE MOIETY