You are using an unsupported browser. Please upgrade your browser to a newer version to get the best experience on DrugBank.
Identification
NameDifenoxin
Accession NumberDB01501
TypeSmall Molecule
GroupsApproved, Illicit
Description

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® 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®. It works mostly in the periphery and activates opioid receptors in the intestine rather than the central nervous system (CNS). 3 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.

Structure
Thumb
Synonyms
1-(3-Cyano-3,3-diphenylpropyl)-4-phenylisonipecotic acid
Difenoxin
Difenoxina
Difenoxinum
Diphenoxilic acid
Diphenoxin
Diphenoxylic acid
External Identifiers
  • McN-JR 15403-11
  • R-15403
Approved Prescription ProductsNot Available
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International Brands
NameCompany
LyspafenJanssen
Brand mixturesNot Available
Salts
Name/CASStructureProperties
Difenoxin hydrochloride
35607-36-4
Thumb
  • InChI Key: VMIZTXDGZPTKIK-UHFFFAOYSA-N
  • Monoisotopic Mass: 460.191755889
  • Average Mass: 460.995
DBSALT000047
Categories
UNII3ZZ5BJ9F2Q
CAS number28782-42-5
WeightAverage: 424.5341
Monoisotopic: 424.21507815
Chemical FormulaC28H28N2O2
InChI KeyInChIKey=UFIVBRCCIRTJTN-UHFFFAOYSA-N
InChI
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)
IUPAC Name
1-(3-cyano-3,3-diphenylpropyl)-4-phenylpiperidine-4-carboxylic acid
SMILES
OC(=O)C1(CCN(CCC(C#N)(C2=CC=CC=C2)C2=CC=CC=C2)CC1)C1=CC=CC=C1
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as diphenylacetonitriles. These are cyclic aromatic compounds containing a diphenylacetonitrile moiety, which consists of a diphenylmethane linked to and acetonitrile to form 2,2-diphenylacetonitrile.
KingdomOrganic compounds
Super ClassBenzenoids
ClassBenzene and substituted derivatives
Sub ClassDiphenylacetonitriles
Direct ParentDiphenylacetonitriles
Alternative Parents
Substituents
  • Diphenylacetonitrile
  • Diphenylmethane
  • Phenylpiperidine
  • Phenylpropylamine
  • Phenylacetate
  • Piperidinecarboxylic acid
  • Benzyl-cyanide
  • Aralkylamine
  • Piperidine
  • Tertiary aliphatic amine
  • Tertiary amine
  • Azacycle
  • Organoheterocyclic compound
  • Nitrile
  • Carbonitrile
  • Monocarboxylic acid or derivatives
  • Carboxylic acid
  • Carboxylic acid derivative
  • Hydrocarbon derivative
  • Organooxygen compound
  • Organonitrogen compound
  • Carbonyl group
  • Amine
  • Aromatic heteromonocyclic compound
Molecular FrameworkAromatic heteromonocyclic compounds
External Descriptors
Pharmacology
IndicationMotofen(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. [2] 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.
PharmacodynamicsDifenoxin acts as a potent antidiarrheal by slowing the movement of the intestines. It also crosses the blood brain barrier to a slight degree to exert weak sedative and analgesic effects. Adverse reactions thus include dizziness, drowsiness, lightheadedness and headache, in addition to gastrointestal side effects such as nausea, vomiting, dry mouth and epigastric distress. [Lexicomp, 2013]
Mechanism of actionDifenoxin 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 [1].
Related Articles
AbsorptionA high percentage of Motofen(R) is absorbed, and absorption occurs rapidly. Peak plasma concentrations are achieved within 40-60 minutes. [Lexicomp, 2013]
Volume of distributionNot Available
Protein bindingNot Available
Metabolism

Metabolism occurs by hydroxylation to form an inactive metabolite. [Lexicomp, 2013]

Route of eliminationBoth the drug and its metabolites are excreted, mainly as conjugates, in urine and feces. [Lexicomp, 2012]
Half lifeThe elimination half life was calculated to be 7.24 hours. The appearance half life was calculated to be 0.82h. [3]
ClearanceNot Available
ToxicityNot Available
Affected organismsNot Available
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9182
Blood Brain Barrier+0.8984
Caco-2 permeable+0.507
P-glycoprotein substrateSubstrate0.6311
P-glycoprotein inhibitor INon-inhibitor0.7353
P-glycoprotein inhibitor IIInhibitor0.5519
Renal organic cation transporterInhibitor0.6229
CYP450 2C9 substrateNon-substrate0.8171
CYP450 2D6 substrateNon-substrate0.6612
CYP450 3A4 substrateNon-substrate0.6411
CYP450 1A2 substrateNon-inhibitor0.8832
CYP450 2C9 inhibitorNon-inhibitor0.8628
CYP450 2D6 inhibitorNon-inhibitor0.6599
CYP450 2C19 inhibitorNon-inhibitor0.8411
CYP450 3A4 inhibitorNon-inhibitor0.6724
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9199
Ames testNon AMES toxic0.8242
CarcinogenicityNon-carcinogens0.9211
BiodegradationNot ready biodegradable0.9849
Rat acute toxicity3.4236 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.827
hERG inhibition (predictor II)Non-inhibitor0.6311
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
ManufacturersNot Available
Packagers
Dosage formsNot Available
PricesNot Available
PatentsNot Available
Properties
StateSolid
Experimental PropertiesNot Available
Predicted Properties
PropertyValueSource
Water Solubility0.00208 mg/mLALOGPS
logP4.39ALOGPS
logP2.65ChemAxon
logS-5.3ALOGPS
pKa (Strongest Acidic)3.38ChemAxon
pKa (Strongest Basic)9.41ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area64.33 Å2ChemAxon
Rotatable Bond Count7ChemAxon
Refractivity137.24 m3·mol-1ChemAxon
Polarizability47.56 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Download (7.02 KB)
SpectraNot Available
References
Synthesis Reference

Soudyn, W. and van Wijngaarden, I.; US. Patent 3,646,207; February 29,1972; assigned to
Janssen Pharrnaceutica, N.V. (Belgium).

General References
  1. De Luca A, Coupar IM: Difenoxin and loperamide: studies on possible mechanisms of intestinal antisecretory action. Naunyn Schmiedebergs Arch Pharmacol. 1993 Feb;347(2):231-7. [PubMed:8386327 ]
  2. Innocenti P, Rossi L, Bombardieri G: [Clinical effectiveness of difenoxine in patients with acute and chronic diarrhea]. Boll Chim Farm. 1983 Dec;122(12):64S-68S. [PubMed:6675727 ]
  3. Jackson LS, Stafford JE: The evaluation and application of a radioimmunoassay for the measurement of diphenoxylic acid, the major metabolite of diphenoxylate hydrochloride (Lomotil), in human plasma. J Pharmacol Methods. 1987 Nov;18(3):189-97. [PubMed:3682841 ]
External Links
ATC CodesA07DA04
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelNot Available
MSDSNot Available
Interactions
Drug Interactions
Drug
AzelastineDifenoxin may increase the central nervous system depressant (CNS depressant) activities of Azelastine.
BaclofenThe risk or severity of adverse effects can be increased when Baclofen is combined with Difenoxin.
BrimonidineBrimonidine may increase the central nervous system depressant (CNS depressant) activities of Difenoxin.
CimetropiumDifenoxin may increase the anticholinergic activities of Cimetropium Bromide.
EluxadolineDifenoxin may increase the activities of Eluxadoline.
EthanolDifenoxin may increase the central nervous system depressant (CNS depressant) activities of Ethanol.
Ipratropium bromideIpratropium bromide may increase the anticholinergic activities of Difenoxin.
LorazepamThe risk or severity of adverse effects can be increased when Lorazepam is combined with Difenoxin.
MorphineThe risk or severity of adverse effects can be increased when Difenoxin is combined with Morphine.
ParoxetineThe risk or severity of adverse effects can be increased when Difenoxin is combined with Paroxetine.
ProcyclidineThe risk or severity of adverse effects can be increased when Procyclidine is combined with Difenoxin.
RamosetronDifenoxin may increase the activities of Ramosetron.
TacrineThe therapeutic efficacy of Difenoxin can be decreased when used in combination with Tacrine.
TrichlormethiazideThe serum concentration of Trichlormethiazide can be increased when it is combined with Difenoxin.
Food Interactions
  • Ethanol use may increase CNS depression.
Comments
comments powered by Disqus
Drug created on July 31, 2007 07:10 / Updated on August 17, 2016 12:23