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Identification
- Summary
Difenoxin is an antidiarrheal agent used as an adjunct for the management of acute nonspecific diarrhea and acute exacerbations of chronic functional diarrhea.
- Brand Names
- Motofen
- Generic Name
- Difenoxin
- DrugBank Accession Number
- DB01501
- Background
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.
- Type
- Small Molecule
- Groups
- Approved, Illicit
- Structure
Structure for Difenoxin (DB01501)
- Weight
- Average: 424.5341
Monoisotopic: 424.21507815 - Chemical Formula
- C28H28N2O2
- Synonyms
- 1-(3-cyano-3,3-diphenylpropyl)-4-phenylisonipecotic acid
- Difenoxin
- Difenoxina
- Difenoxinum
- Diphenoxilic acid
- Diphenoxylic acid
- External IDs
- IDS-ND-007
- McN-JR 15403-11
- MCN-JR-15,403-11
- R 15,403
- R-15403
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.
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Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Used as adjunct in combination to manage Diarrhea Combination Product in combination with: Atropine (DB00572) •••••••••••• Used as adjunct in combination to manage Diarrhea Regimen in combination with: Atropine (DB00572) •••••••••••• Used as adjunct in combination to manage Acute exacerbations of functional diarrhea Regimen in combination with: Atropine (DB00572) •••••••••••• - Contraindications & Blackbox Warnings
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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
- Adverse Effects
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Not Available
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Integrate drug-drug
interactions in your software1,2-Benzodiazepine The risk or severity of CNS depression can be increased when Difenoxin is combined with 1,2-Benzodiazepine. Acetazolamide The risk or severity of CNS depression can be increased when Acetazolamide is combined with Difenoxin. Acetophenazine The risk or severity of CNS depression can be increased when Acetophenazine is combined with Difenoxin. Agomelatine The risk or severity of CNS depression can be increased when Difenoxin is combined with Agomelatine. Alfentanil The risk or severity of CNS depression can be increased when Alfentanil is combined with Difenoxin. - Food Interactions
- Avoid alcohol. Alcohol can enhance the CNS depressant effects of this drug.
Products
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Ingredient UNII CAS InChI Key Difenoxin hydrochloride VQZ63K01IW 35607-36-4 VMIZTXDGZPTKIK-UHFFFAOYSA-N - International/Other Brands
- Lyspafen (Janssen)
- Mixture Products
Name Ingredients Dosage Route Labeller Marketing Start Marketing End Region Image Motofen Difenoxin hydrochloride (1 mg/1) + Atropine sulfate (0.025 mg/1) Tablet Oral Physicians Total Care, Inc. 1962-07-14 2010-06-30 US 
Motofen Difenoxin hydrochloride (1 mg/1) + Atropine sulfate (0.025 mg/1) Tablet Oral Valeant Pharmaceuticals North America LLC 1962-07-14 2014-11-30 US Motofen Difenoxin hydrochloride (1 mg/1) + Atropine sulfate (0.025 mg/1) Tablet Oral Sebela Pharmaceuticals Inc. 2017-04-11 Not applicable US
Categories
- ATC Codes
- A07DA04 — Difenoxin
- Drug Categories
- Chemical TaxonomyProvided by Classyfire
- 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
- Amine / Amino acid / Amino acid or derivatives / Aralkylamine / Aromatic heteromonocyclic compound / Azacycle / Carbonitrile / Carbonyl group / Carboxylic acid / Carboxylic acid derivative show 17 more
- Molecular Framework
- Aromatic heteromonocyclic compounds
- External Descriptors
- tertiary amine, piperidinemonocarboxylic acid, nitrile (CHEBI:4534)
- Affected organisms
- Not Available
Chemical Identifiers
- UNII
- 3ZZ5BJ9F2Q
- CAS number
- 28782-42-5
- 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
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
- 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. [Article]
- 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. [Article]
- 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. [Article]
- External Links
- KEGG Drug
- D03809
- KEGG Compound
- C07871
- PubChem Compound
- 34328
- PubChem Substance
- 46508854
- ChemSpider
- 31620
- 23024
- ChEBI
- 4534
- ChEMBL
- CHEMBL1201321
- ZINC
- ZINC000000601317
- RxList
- RxList Drug Page
- Drugs.com
- Drugs.com Drug Page
- PDRhealth
- PDRhealth Drug Page
- Wikipedia
- Difenoxin
Clinical Trials
- Clinical Trials
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Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Amarin Pharmaceuticals
- Dispensing Solutions
- Physicians Total Care Inc.
- Valeant Ltd.
- West-Ward Pharmaceuticals
- Dosage Forms
Form Route Strength Tablet Oral - Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Solid
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source Water Solubility 0.00208 mg/mL ALOGPS logP 4.39 ALOGPS logP 2.65 Chemaxon logS -5.3 ALOGPS pKa (Strongest Acidic) 3.38 Chemaxon pKa (Strongest Basic) 9.41 Chemaxon Physiological Charge 0 Chemaxon Hydrogen Acceptor Count 4 Chemaxon Hydrogen Donor Count 1 Chemaxon Polar Surface Area 64.33 Å2 Chemaxon Rotatable Bond Count 7 Chemaxon Refractivity 137.24 m3·mol-1 Chemaxon Polarizability 47.59 Å3 Chemaxon Number of Rings 4 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter No Chemaxon Veber's Rule No Chemaxon MDDR-like Rule Yes Chemaxon - Predicted ADMET Features
Property Value Probability Human Intestinal Absorption + 0.9182 Blood Brain Barrier + 0.8984 Caco-2 permeable + 0.507 P-glycoprotein substrate Substrate 0.6311 P-glycoprotein inhibitor I Non-inhibitor 0.7353 P-glycoprotein inhibitor II Inhibitor 0.5519 Renal organic cation transporter Inhibitor 0.6229 CYP450 2C9 substrate Non-substrate 0.8171 CYP450 2D6 substrate Non-substrate 0.6612 CYP450 3A4 substrate Non-substrate 0.6411 CYP450 1A2 substrate Non-inhibitor 0.8832 CYP450 2C9 inhibitor Non-inhibitor 0.8628 CYP450 2D6 inhibitor Non-inhibitor 0.6599 CYP450 2C19 inhibitor Non-inhibitor 0.8411 CYP450 3A4 inhibitor Non-inhibitor 0.6724 CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.9199 Ames test Non AMES toxic 0.8242 Carcinogenicity Non-carcinogens 0.9211 Biodegradation Not ready biodegradable 0.9849 Rat acute toxicity 3.4236 LD50, mol/kg Not applicable hERG inhibition (predictor I) Weak inhibitor 0.827 hERG inhibition (predictor II) Non-inhibitor 0.6311
Spectra
- Mass Spec (NIST)
- Download (7.02 KB)
- Spectra
Spectrum Spectrum Type Splash Key Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS splash10-004i-0003900000-1f61922d3902808e03f5 Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS splash10-0ufr-0009200000-b55c7109081f8f58e711 Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS splash10-00di-0003900000-e3f15bc0c041b7f099ee Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS splash10-0uk9-0009200000-b8abc169d6a6259fb324 Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS splash10-002f-0925300000-904966ce45f4d45bb15b Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS splash10-014i-1669100000-c1bcf92cffdfc5d5f3c3 Predicted 1H NMR Spectrum 1D NMR Not Applicable Predicted 13C NMR Spectrum 1D NMR Not Applicable - Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 214.6956043 predictedDarkChem Lite v0.1.0 [M-H]- 199.54117 predictedDeepCCS 1.0 (2019) [M+H]+ 214.7311043 predictedDarkChem Lite v0.1.0 [M+H]+ 201.89919 predictedDeepCCS 1.0 (2019) [M+Na]+ 214.9167043 predictedDarkChem Lite v0.1.0 [M+Na]+ 208.06139 predictedDeepCCS 1.0 (2019)
Drug created at July 31, 2007 13:10 / Updated at August 02, 2024 07:31