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Identification
NameDiphenoxylate
Accession NumberDB01081  (APRD00366)
TypeSmall Molecule
GroupsApproved, Illicit
Description

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.

Structure
Thumb
Synonyms
SynonymLanguageCode
1-(3-Cyano-3,3-diphenylpropyl)-4-phenyl-isonipecotic acid ethyl esterNot AvailableNot Available
2,2-Diphenyl-4-(4-carbethoxy-4-phenylpiperidino)butyronitrileNot AvailableNot Available
4-Ethoxycarbonyl-alpha,alpha,4-triphenyl-1-piperidinebutyronitrileNot AvailableNot Available
DifenossilatoNot AvailableDCIT
DifenoxilatoSpanishINN
DiphenoxylatumLatinINN
Ethyl 1-(3-cyano-3,3-diphenylpropyl)-4-phenyl-4-piperidinecarboxylateNot AvailableNot Available
Ethyl 1-(3-cyano-3,3-diphenylpropyl)-4-phenylisonipecotateNot AvailableNot Available
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Lomotiltablet.025; 2.5 mg/1; mgoralG.D. Searle LLC Division of Pfizer Inc1960-09-15Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Lomotiltablet.025; 2.5 mg/1; mgoralPhysicians Total Care, Inc.2009-01-19Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Generic Prescription ProductsNot Available
Over the Counter ProductsNot Available
International BrandsNot Available
Brand mixtures
Brand NameIngredients
Co-PhenotropeDiphenoxylate + Atropine
LomotilAtropine Sulfate + Diphenoxylate Hcl
Salts
Name/CASStructureProperties
Diphenoxylate Hydrochloride
Thumb
  • InChI Key: SHTAFWKOISOCBI-UHFFFAOYSA-N
  • Monoisotopic Mass: 488.223056017
  • Average Mass: 489.048
DBSALT000809
Categories
CAS number915-30-0
WeightAverage: 452.5873
Monoisotopic: 452.246378278
Chemical FormulaC30H32N2O2
InChI KeyHYPPXZBJBPSRLK-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
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
  • Carboxylic acid ester
  • Azacycle
  • Organoheterocyclic compound
  • Nitrile
  • Carbonitrile
  • Monocarboxylic acid or derivatives
  • Carboxylic acid derivative
  • Hydrocarbon derivative
  • Organooxygen compound
  • Organonitrogen compound
  • Carbonyl group
  • Amine
  • Aromatic heteromonocyclic compound
Molecular FrameworkAromatic heteromonocyclic compounds
External Descriptors
Pharmacology
IndicationFor as adjunctive therapy in the management of diarrhea
PharmacodynamicsDiphenoxylate, 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 actionDiphenoxylate 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.
Absorption90%
Volume of distributionNot Available
Protein binding74-95%
Metabolism

Hepatic

Route of eliminationNot Available
Half life12-14 hours
ClearanceNot Available
ToxicityComa, 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
Affected organisms
  • Humans and other mammals
Pathways
PathwayCategorySMPDB ID
Diphenoxylate Action PathwayDrug actionSMP00675
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
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 substrateInhibitor0.6701
CYP450 2D6 substrateInhibitor0.6461
CYP450 2C19 substrateInhibitor0.51
CYP450 3A4 substrateInhibitor0.5797
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
Pharmacoeconomics
ManufacturersNot Available
Packagers
Dosage forms
FormRouteStrength
Tabletoral.025; 2.5 mg/1; mg
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.
PatentsNot Available
Properties
StateSolid
Experimental Properties
PropertyValueSource
melting point220.5-222Janssen, 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 FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraMS
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 ReferenceNot Available
External Links
ATC CodesA07DA01
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelNot Available
MSDSDownload (49.7 KB)
Interactions
Drug Interactions
Drug
AclidiniumMay enhance the anticholinergic effect of Anticholinergic Agents.
BuprenorphineCNS Depressants may enhance the CNS depressant effect of Buprenorphine.
DoxylamineMay enhance the CNS depressant effect of CNS Depressants.
DronabinolMay enhance the CNS depressant effect of CNS Depressants.
DroperidolMay enhance the CNS depressant effect of CNS Depressants.
HydrocodoneCNS Depressants may enhance the CNS depressant effect of Hydrocodone.
HydroxyzineMay enhance the CNS depressant effect of CNS Depressants.
ItoprideAnticholinergic Agents may diminish the therapeutic effect of Itopride.
Magnesium SulfateMay enhance the CNS depressant effect of CNS Depressants.
MethotrimeprazineCNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants.
MetoclopramideAnticholinergic Agents may diminish the therapeutic effect of Metoclopramide.
MetyrosineCNS Depressants may enhance the sedative effect of Metyrosine.
MianserinMay enhance the anticholinergic effect of Anticholinergic Agents.
MirabegronAnticholinergic Agents may enhance the adverse/toxic effect of Mirabegron.
MirtazapineCNS Depressants may enhance the CNS depressant effect of Mirtazapine.
NabiloneMay enhance the CNS depressant effect of CNS Depressants.
OrphenadrineCNS Depressants may enhance the CNS depressant effect of Orphenadrine.
PerampanelMay enhance the CNS depressant effect of CNS Depressants.
Potassium ChlorideAnticholinergic Agents may enhance the ulcerogenic effect of Potassium Chloride.
PramipexoleCNS Depressants may enhance the sedative effect of Pramipexole.
PramlintideMay enhance the anticholinergic effect of Anticholinergic Agents. These effects are specific to the GI tract.
RopiniroleCNS Depressants may enhance the sedative effect of ROPINIRole.
RotigotineCNS Depressants may enhance the sedative effect of Rotigotine.
RufinamideMay enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced.
SecretinAnticholinergic Agents may diminish the therapeutic effect of Secretin.
SuvorexantCNS Depressants may enhance the CNS depressant effect of Suvorexant.
TapentadolMay enhance the CNS depressant effect of CNS Depressants.
ThalidomideCNS Depressants may enhance the CNS depressant effect of Thalidomide.
TiotropiumAnticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
TopiramateAnticholinergic Agents may enhance the adverse/toxic effect of Topiramate.
ZolpidemCNS Depressants may enhance the CNS depressant effect of Zolpidem.
Food Interactions
  • Avoid alcohol.
  • Take with food.

Targets

1. Mu-type opioid receptor

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: agonist

Components

Name UniProt ID Details
Mu-type opioid receptor P35372 Details

References:

  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  2. Baker DE: Loperamide: a pharmacological review. Rev Gastroenterol Disord. 2007;7 Suppl 3:S11-8. Pubmed
  3. Corazziari E: Role of opioid ligands in the irritable bowel syndrome. Can J Gastroenterol. 1999 Mar;13 Suppl A:71A-75A. Pubmed
  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. Pubmed
  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. Pubmed

2. Delta-type opioid receptor

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: agonist

Components

Name UniProt ID Details
Delta-type opioid receptor P41143 Details

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. Pubmed

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Drug created on June 13, 2005 07:24 / Updated on April 15, 2014 11:41