NAV

Diphenoxylate

Identification

Summary

Diphenoxylate is an antidiarrheal medication used with atropine to manage diarrhea.

Brand Names
Lomotil
Generic Name
Diphenoxylate
DrugBank Accession Number
DB01081
Background

A meperidine congener used as an antidiarrheal, usually in combination with atropine. At high doses, it acts like morphine. Its unesterified metabolite difenoxin has similar properties and is used similarly. It has little or no analgesic activity. This medication is classified as a Schedule V under the Controlled Substances Act by the Food and Drug Administration (FDA) and the DEA in the United States when used in preparations. When diphenoxylate is used alone, it is classified as a Schedule II.

Type
Small Molecule
Groups
Approved, Illicit
Structure
3D
Similar Structures
Weight
Average: 452.5873
Monoisotopic: 452.246378278
Chemical Formula
C30H32N2O2
Synonyms
  • 1-(3-Cyano-3,3-diphenylpropyl)-4-phenyl-isonipecotic acid ethyl ester
  • 2,2-Diphenyl-4-(4-carbethoxy-4-phenylpiperidino)butyronitrile
  • Difenossilato
  • Difenoxilato
  • Diphenoxylate
  • Diphenoxylatum
  • Ethyl 1-(3-cyano-3,3-diphenylpropyl)-4-phenyl-4-piperidinecarboxylate
  • Ethyl 1-(3-cyano-3,3-diphenylpropyl)-4-phenylisonipecotate
External IDs
  • DEA No. 9170
  • IDS-ND-016
  • R-1132

Pharmacology

Indication

For as adjunctive therapy in the management of diarrhea

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Associated Conditions
Contraindications & Blackbox Warnings
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Pharmacodynamics

Diphenoxylate, an antidiarrheal, is effective as adjunctive therapy in the management of diarrhea. Diphenoxylate is rapidly and extensively metabolized in man by ester hydrolysis to diphenoxylic acid (difenoxine), which is biologically active and the major metabolite in the blood.

Mechanism of action

Diphenoxylate is an opiate receptor agonists that stimulate mu receptors in GI to decrease the peristalsis and constrict the sphincters. Diphenoxylate has a direct effect on circular smooth muscle of the bowel, that conceivably results in segmentation and prolongation of gastrointestinal transit time. The clinical antidiarrheal action of diphenoxylate may thus be a consequence of enhanced segmentation that allows increased contact of the intraluminal contents with the intestinal mucosa.

TargetActionsOrganism
AMu-type opioid receptor
agonist
Humans
UDelta-type opioid receptor
agonist
Humans
Absorption

90%

Volume of distribution

Not Available

Protein binding

74-95%

Metabolism

Hepatic

Route of elimination

Not Available

Half-life

12-14 hours

Clearance

Not Available

Adverse Effects
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Toxicity

Coma, dry skin and mucous membranes, enlarged pupils of the eyes, extremely high body temperature, flushing, involuntary eyeball movement, lower than normal muscle tone, pinpoint pupils, rapid heartbeat, restlessness, sluggishness, suppressed breathing

Pathways
PathwayCategory
Diphenoxylate Action PathwayDrug action
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.
DrugInteraction
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1,2-BenzodiazepineThe risk or severity of adverse effects can be increased when Diphenoxylate is combined with 1,2-Benzodiazepine.
AcetazolamideThe risk or severity of adverse effects can be increased when Acetazolamide is combined with Diphenoxylate.
AcetophenazineThe risk or severity of hypotension and CNS depression can be increased when Acetophenazine is combined with Diphenoxylate.
AclidiniumThe risk or severity of adverse effects can be increased when Aclidinium is combined with Diphenoxylate.
AgomelatineThe risk or severity of adverse effects can be increased when Diphenoxylate is combined with Agomelatine.
AlfentanilThe risk or severity of adverse effects can be increased when Alfentanil is combined with Diphenoxylate.
AlimemazineThe risk or severity of hypotension and CNS depression can be increased when Alimemazine is combined with Diphenoxylate.
AlloinThe therapeutic efficacy of Alloin can be decreased when used in combination with Diphenoxylate.
AlmotriptanThe risk or severity of adverse effects can be increased when Almotriptan is combined with Diphenoxylate.
AlosetronThe risk or severity of adverse effects can be increased when Alosetron is combined with Diphenoxylate.
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Food Interactions
  • Avoid alcohol.
  • Take with food.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Diphenoxylate hydrochlorideW24OD7YW483810-80-8SHTAFWKOISOCBI-UHFFFAOYSA-N
Product Images
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
BEAMOTIL TABLETSDiphenoxylate hydrochloride (2.5 mg) + Atropine sulfate anhydrous (0.025 mg)Tablet, film coatedOralBEACONS PHARMACEUTICALS PTE. LTD.1991-06-01Not applicable
DHAMOTIL TABLETDiphenoxylate hydrochloride (2.5 mg) + Atropine sulfate anhydrous (0.025 mg)Tablet, film coatedOralTEVA PHARMACEUTICAL INVESTMENTS SINGAPORE PTE. LTD.1991-01-29Not applicable
Diphenoxylate Hcl and Atropine SulfateDiphenoxylate hydrochloride (2.5 mg/1) + Atropine sulfate (0.025 mg/1)TabletOralStat Rx USA1979-10-29Not applicableUS flag
Diphenoxylate Hydrochloride and Atropine SulfateDiphenoxylate hydrochloride (2.5 mg/1) + Atropine sulfate (0.025 mg/1)TabletOralAidarex Pharmaceuticals LLC2010-11-30Not applicableUS flag
Diphenoxylate Hydrochloride and Atropine SulfateDiphenoxylate hydrochloride (2.5 mg/1) + Atropine sulfate (0.025 mg/1)TabletOralUnit Dose Services2013-02-272017-12-31US flag
Diphenoxylate Hydrochloride and Atropine SulfateDiphenoxylate hydrochloride (2.5 mg/1) + Atropine sulfate (0.025 mg/1)TabletOralRpk Pharmaceuticals, Inc.2020-03-15Not applicableUS flag
Diphenoxylate Hydrochloride and Atropine SulfateDiphenoxylate hydrochloride (2.5 mg/1) + Atropine sulfate (0.025 mg/1)TabletOralbryant ranch prepack2017-07-07Not applicableUS flag
Diphenoxylate Hydrochloride and Atropine SulfateDiphenoxylate hydrochloride (2.5 mg/1) + Atropine sulfate (0.025 mg/1)TabletOralA-S Medication Solutions2020-03-15Not applicableUS flag
Diphenoxylate Hydrochloride and Atropine SulfateDiphenoxylate hydrochloride (2.5 mg/1) + Atropine sulfate (0.025 mg/1)TabletOralDispensing Solutions, Inc.2010-11-30Not applicableUS flag
Diphenoxylate Hydrochloride and Atropine SulfateDiphenoxylate hydrochloride (2.5 mg/1) + Atropine sulfate (0.025 mg/1)TabletOralAphena Pharma Solutions - Tennessee, LLC2017-06-20Not applicableUS flag

Categories

ATC Codes
A07DA01 — Diphenoxylate
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 / Carboxylic acid esters / Amino acids and derivatives / Nitriles / Monocarboxylic acids and derivatives / Azacyclic compounds
show 4 more
Substituents
Amine / Amino acid or derivatives / Aralkylamine / Aromatic heteromonocyclic compound / Azacycle / Carbonitrile / Carbonyl group / Carboxylic acid derivative / Carboxylic acid ester / Diphenylacetonitrile
show 16 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
ethyl ester, tertiary amine, nitrile, piperidinecarboxylate ester (CHEBI:4639)
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
73312P173G
CAS number
915-30-0
InChI Key
HYPPXZBJBPSRLK-UHFFFAOYSA-N
InChI
InChI=1S/C30H32N2O2/c1-2-34-28(33)29(25-12-6-3-7-13-25)18-21-32(22-19-29)23-20-30(24-31,26-14-8-4-9-15-26)27-16-10-5-11-17-27/h3-17H,2,18-23H2,1H3
IUPAC Name
ethyl 1-(3-cyano-3,3-diphenylpropyl)-4-phenylpiperidine-4-carboxylate
SMILES
CCOC(=O)C1(CCN(CCC(C#N)(C2=CC=CC=C2)C2=CC=CC=C2)CC1)C1=CC=CC=C1

References

Synthesis Reference

Janssen, P.A.J.; U.S.Patent 2,898,340; August 4,1959. Dryden, H.L. Jr. and Erickson, R.A.; U.S. Patent 4,086,234; April 25,1978; assigned to G.D.Searle & Co.

General References
Not Available
Human Metabolome Database
HMDB0015213
KEGG Drug
D00301
KEGG Compound
C07872
PubChem Compound
13505
PubChem Substance
46507130
ChemSpider
12919
BindingDB
50401672
RxNav
3500
ChEBI
4639
ChEMBL
CHEMBL1201294
ZINC
ZINC000003830716
Therapeutic Targets Database
DAP001136
PharmGKB
PA164746539
RxList
RxList Drug Page
Wikipedia
Diphenoxylate
MSDS
Download (49.7 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3CompletedDiagnosticLymphoma1
2CompletedTreatmentBreast Adenocarcinoma / HER2/Neu-positive Breast Cancer / Stage II Breast Cancer AJCC v6 and v7 / Stage IIA Breast Cancer AJCC v6 and v7 / Stage IIB Breast Cancer AJCC v6 and v7 / Stage III Breast Cancer AJCC V7 / Stage IIIA Breast Cancer AJCC v7 / Stage IIIB Breast Cancer AJCC v7 / Stage IIIC Breast Cancer AJCC v71

Pharmacoeconomics

Manufacturers
Not Available
Packagers
  • Amerisource Health Services Corp.
  • Amneal Pharmaceuticals
  • A-S Medication Solutions LLC
  • Bryant Ranch Prepack
  • Cardinal Health
  • Caremark LLC
  • Comprehensive Consultant Services Inc.
  • Direct Dispensing Inc.
  • Dispensing Solutions
  • Diversified Healthcare Services Inc.
  • Eon Labs
  • GD Searle LLC
  • Group Health Cooperative
  • H.J. Harkins Co. Inc.
  • Heartland Repack Services LLC
  • Ivax Pharmaceuticals
  • Kaiser Foundation Hospital
  • Keltman Pharmaceuticals Inc.
  • Lake Erie Medical and Surgical Supply
  • Lannett Co. Inc.
  • Murfreesboro Pharmaceutical Nursing Supply
  • Mylan
  • Nucare Pharmaceuticals Inc.
  • Palmetto Pharmaceuticals Inc.
  • Patient First Corp.
  • PCA LLC
  • PD-Rx Pharmaceuticals Inc.
  • Pharmacia Inc.
  • Pharmedix
  • Physicians Total Care Inc.
  • Preferred Pharmaceuticals Inc.
  • Prepackage Specialists
  • Prepak Systems Inc.
  • Rebel Distributors Corp.
  • Redpharm Drug
  • Remedy Repack
  • Roxane Labs
  • Sandhills Packaging Inc.
  • Sandoz
  • St Mary's Medical Park Pharmacy
  • UDL Laboratories
  • Va Cmop Dallas
Dosage Forms
FormRouteStrength
Tablet, film coatedOral0.025 mg
Tablet, film coatedOral
SolutionOral
TabletOral
TabletOral2.5 mg
LiquidOral
Tablet
Tablet2.5 mg/0.025mg
TabletOral0.025 mg
SyrupOral0.025 mg/5ml
Prices
Unit descriptionCostUnit
Lomotil 2.5-0.025 mg/5ml Liquid 60ml Bottle30.86USD bottle
Lomotil 2.5-0.025 mg tablet1.4USD tablet
Lomotil tablet1.12USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)220.5-222Janssen, P.A.J.; U.S.Patent 2,898,340; August 4,1959. Dryden, H.L. Jr. and Erickson, R.A.; U.S. Patent 4,086,234; April 25,1978; assigned to G.D.Searle & Co.
water solubility800 mg/L (at 25 °C)MERCK INDEX (1996)
logP6.3Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.00146 mg/mLALOGPS
logP5.74ALOGPS
logP5.88Chemaxon
logS-5.5ALOGPS
pKa (Strongest Basic)8.5Chemaxon
Physiological Charge1Chemaxon
Hydrogen Acceptor Count3Chemaxon
Hydrogen Donor Count0Chemaxon
Polar Surface Area53.33 Å2Chemaxon
Rotatable Bond Count9Chemaxon
Refractivity146.76 m3·mol-1Chemaxon
Polarizability51.58 Å3Chemaxon
Number of Rings4Chemaxon
Bioavailability1Chemaxon
Rule of FiveNoChemaxon
Ghose FilterNoChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleYesChemaxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.9903
Blood Brain Barrier+0.9592
Caco-2 permeable+0.5316
P-glycoprotein substrateSubstrate0.7094
P-glycoprotein inhibitor IInhibitor0.7045
P-glycoprotein inhibitor IIInhibitor0.7845
Renal organic cation transporterInhibitor0.5967
CYP450 2C9 substrateNon-substrate0.8333
CYP450 2D6 substrateNon-substrate0.5667
CYP450 3A4 substrateNon-substrate0.5988
CYP450 1A2 substrateNon-inhibitor0.6827
CYP450 2C9 inhibitorInhibitor0.6701
CYP450 2D6 inhibitorInhibitor0.6461
CYP450 2C19 inhibitorInhibitor0.51
CYP450 3A4 inhibitorInhibitor0.5797
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.817
Ames testNon AMES toxic0.8482
CarcinogenicityNon-carcinogens0.839
BiodegradationNot ready biodegradable0.9805
Rat acute toxicity3.3423 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.7969
hERG inhibition (predictor II)Inhibitor0.592
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
GC-MS Spectrum - EI-BGC-MSsplash10-0002-6591000000-e04da61bbde263b104e3
Mass Spectrum (Electron Ionization)MSsplash10-0002-2390000000-0d133bb29f340639db02
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
LC-MS/MS Spectrum - LC-ESI-QTOF , positiveLC-MS/MSsplash10-0udi-0000900000-e2841fe11576faaa404e
LC-MS/MS Spectrum - LC-ESI-QTOF , positiveLC-MS/MSsplash10-0udi-0000900000-f16aa8a859221ed0173c
LC-MS/MS Spectrum - LC-ESI-QTOF , positiveLC-MS/MSsplash10-0udi-0220900000-38d21080081c6d144498
LC-MS/MS Spectrum - LC-ESI-QTOF , positiveLC-MS/MSsplash10-0ap0-2920000000-ed4957b090e4b3a6f38d
LC-MS/MS Spectrum - LC-ESI-QTOF , positiveLC-MS/MSsplash10-0aor-2900000000-becb90ead622a0131fdb
MS/MS Spectrum - , positiveLC-MS/MSsplash10-0udi-0210900000-f33819852c9168d0f8a0

Targets

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Details1. Mu-type opioid receptor
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
General Function
Voltage-gated calcium channel activity
Specific Function
Receptor for endogenous opioids such as beta-endorphin and endomorphin. Receptor for natural and synthetic opioids including morphine, heroin, DAMGO, fentanyl, etorphine, buprenorphin and methadone...
Gene Name
OPRM1
Uniprot ID
P35372
Uniprot Name
Mu-type opioid receptor
Molecular Weight
44778.855 Da
References
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
  2. Baker DE: Loperamide: a pharmacological review. Rev Gastroenterol Disord. 2007;7 Suppl 3:S11-8. [Article]
  3. Corazziari E: Role of opioid ligands in the irritable bowel syndrome. Can J Gastroenterol. 1999 Mar;13 Suppl A:71A-75A. [Article]
  4. Coupar IM: The peristaltic reflex in the rat ileum: evidence for functional mu- and delta-opiate receptors. J Pharm Pharmacol. 1995 Aug;47(8):643-6. [Article]
  5. 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]
Details2. Delta-type opioid receptor
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Agonist
General Function
Opioid receptor activity
Specific Function
G-protein coupled receptor that functions as receptor for endogenous enkephalins and for a subset of other opioids. Ligand binding causes a conformation change that triggers signaling via guanine n...
Gene Name
OPRD1
Uniprot ID
P41143
Uniprot Name
Delta-type opioid receptor
Molecular Weight
40368.235 Da
References
  1. Coupar IM: The peristaltic reflex in the rat ileum: evidence for functional mu- and delta-opiate receptors. J Pharm Pharmacol. 1995 Aug;47(8):643-6. [Article]

Drug created at June 13, 2005 13:24 / Updated at May 02, 2022 10:05