Difenoxin

Identification

Name
Difenoxin
Accession Number
DB01501
Type
Small Molecule
Groups
Approved, 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(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). [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 IDs
IDS-ND-007 / McN-JR 15403-11 / MCN-JR-15,403-11 / R 15,403 / R-15403
Product Ingredients
IngredientUNIICASInChI Key
Difenoxin hydrochlorideVQZ63K01IW35607-36-4VMIZTXDGZPTKIK-UHFFFAOYSA-N
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
MotofenDifenoxin hydrochloride (1 mg/1) + Atropine Sulfate (0.025 mg/1)TabletOralValeant Pharmaceuticals North America1962-07-142014-11-30Us
MotofenDifenoxin hydrochloride (1 mg/1) + Atropine Sulfate (0.025 mg/1)TabletOralSebela Pharmaceuticals Inc.2017-04-11Not applicableUs
MotofenDifenoxin hydrochloride (1 mg/1) + Atropine Sulfate (0.025 mg/1)TabletOralPhysicians Total Care, Inc.1962-07-142010-06-30Us
International/Other Brands
Lyspafen (Janssen)
Categories
UNII
3ZZ5BJ9F2Q
CAS number
28782-42-5
Weight
Average: 424.5341
Monoisotopic: 424.21507815
Chemical Formula
C28H28N2O2
InChI Key
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

Pharmacology

Indication

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. [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.

Associated Conditions
Pharmacodynamics

Difenoxin 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 action

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 [1].

Absorption

A high percentage of Motofen(R) is absorbed, and absorption occurs rapidly. Peak plasma concentrations are achieved within 40-60 minutes. [Lexicomp, 2013]

Volume of distribution
Not Available
Protein binding
Not Available
Metabolism

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

Route of elimination

Both the drug and its metabolites are excreted, mainly as conjugates, in urine and feces. [Lexicomp, 2012]

Half life

The elimination half life was calculated to be 7.24 hours. The appearance half life was calculated to be 0.82h. [3]

Clearance
Not Available
Toxicity
Not Available
Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
7-NitroindazoleThe risk or severity of adverse effects can be increased when Difenoxin is combined with 7-Nitroindazole.
AcepromazineThe risk or severity of adverse effects can be increased when Difenoxin is combined with Acepromazine.
AceprometazineThe risk or severity of adverse effects can be increased when Difenoxin is combined with Aceprometazine.
AcetazolamideThe risk or severity of adverse effects can be increased when Difenoxin is combined with Acetazolamide.
AdipiplonThe risk or severity of adverse effects can be increased when Difenoxin is combined with Adipiplon.
AgomelatineThe risk or severity of adverse effects can be increased when Difenoxin is combined with Agomelatine.
AlaproclateThe risk or severity of adverse effects can be increased when Difenoxin is combined with Alaproclate.
AlfaxaloneThe risk or severity of adverse effects can be increased when Difenoxin is combined with Alfaxalone.
AlfentanilThe risk or severity of adverse effects can be increased when Alfentanil is combined with Difenoxin.
AlimemazineThe risk or severity of adverse effects can be increased when Difenoxin is combined with Alimemazine.
Food Interactions
  • Ethanol use may increase CNS depression.

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
KEGG Drug
D03809
KEGG Compound
C07871
PubChem Compound
34328
PubChem Substance
46508854
ChemSpider
31620
ChEBI
4534
ChEMBL
CHEMBL1201321
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
PDRhealth
PDRhealth Drug Page
Wikipedia
Difenoxin
ATC Codes
A07DA04 — Difenoxin

Clinical Trials

Clinical Trials
Not Available

Pharmacoeconomics

Manufacturers
Not Available
Packagers
  • Amarin Pharmaceuticals
  • Dispensing Solutions
  • Physicians Total Care Inc.
  • Valeant Ltd.
  • West-Ward Pharmaceuticals
Dosage forms
FormRouteStrength
TabletOral
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not 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 FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
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)

Spectra

Mass Spec (NIST)
Download (7.02 KB)
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This 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.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
Diphenylacetonitriles
Direct Parent
Diphenylacetonitriles
Alternative Parents
Diphenylmethanes / Phenylpiperidines / Piperidinecarboxylic acids / Aralkylamines / Trialkylamines / Amino acids / Nitriles / Monocarboxylic acids and derivatives / Carboxylic acids / Azacyclic compounds
show 4 more
Substituents
Diphenylacetonitrile / Diphenylmethane / Phenylpiperidine / Piperidinecarboxylic acid / Aralkylamine / Piperidine / Amino acid or derivatives / Amino acid / Tertiary aliphatic amine / Tertiary amine
show 17 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
tertiary amine, piperidinemonocarboxylic acid, nitrile (CHEBI:4534)

Drug created on July 31, 2007 07:10 / Updated on October 01, 2018 16:22