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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
Salts
Name/CAS Structure Properties
Diphenoxylate Hydrochloride
Thumb
  • InChI Key: SHTAFWKOISOCBI-UHFFFAOYSA-N
  • Monoisotopic Mass: 488.223056017
  • Average Mass: 489.048
DBSALT000809
Brand names
NameCompany
LomotilJohnson & Johnson
Brand mixtures
Brand NameIngredients
Co-PhenotropeDiphenoxylate + Atropine
LomotilAtropine Sulfate + Diphenoxylate Hcl
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
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassBenzenoids
ClassBenzene and Substituted Derivatives
SubclassDiphenylacetonitriles
Direct parentDiphenylacetonitriles
Alternative parentsDiphenylmethanes; Phenylpiperidines; Phenylacetic Acid Derivatives; Phenylpropylamines; Benzyl Cyanides; Piperidinecarboxylic Acids; Carboxylic Acid Esters; Tertiary Amines; Ethers; Polyamines; Nitriles; Enolates
Substituentsdiphenylmethane; phenylpiperidine; phenylacetate; phenylpropylamine; benzyl-cyanide; piperidinecarboxylic acid; piperidine; carboxylic acid ester; tertiary amine; carbonitrile; polyamine; nitrile; ether; carboxylic acid derivative; enolate; amine; organonitrogen compound
Classification descriptionThis compound belongs to the diphenylacetonitriles. These are cyclic aromatic compounds containing a diphenylacetonitrile moeity, which consists of a diphenylmethane linked to and acetonitrile to form 2,2-diphenylacetonitrile.
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
Property Value Probability
Human Intestinal Absorption + 0.9903
Blood Brain Barrier + 0.9592
Caco-2 permeable + 0.5316
P-glycoprotein substrate Substrate 0.7094
P-glycoprotein inhibitor I Inhibitor 0.7045
P-glycoprotein inhibitor II Inhibitor 0.7845
Renal organic cation transporter Inhibitor 0.5967
CYP450 2C9 substrate Non-substrate 0.8333
CYP450 2D6 substrate Non-substrate 0.5667
CYP450 3A4 substrate Non-substrate 0.5988
CYP450 1A2 substrate Non-inhibitor 0.6827
CYP450 2C9 substrate Inhibitor 0.6701
CYP450 2D6 substrate Inhibitor 0.6461
CYP450 2C19 substrate Inhibitor 0.51
CYP450 3A4 substrate Inhibitor 0.5797
CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.817
Ames test Non AMES toxic 0.8482
Carcinogenicity Non-carcinogens 0.839
Biodegradation Not ready biodegradable 0.9805
Rat acute toxicity 3.3423 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.7969
hERG inhibition (predictor II) Inhibitor 0.592
Pharmacoeconomics
ManufacturersNot Available
Packagers
Dosage forms
FormRouteStrength
SolutionOral
TabletOral
Prices
Unit descriptionCostUnit
Lomotil 2.5-0.025 mg/5ml Liquid 60ml Bottle30.86USDbottle
Lomotil 2.5-0.025 mg tablet1.4USDtablet
Lomotil tablet1.12USDtablet
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 Solubility0.00146ALOGPS
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
Spectra
Spectra
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
ResourceLink
KEGG DrugD00301
PubChem Compound13505
PubChem Substance46507130
ChemSpider12919
Therapeutic Targets DatabaseDAP001136
PharmGKBPA164746539
RxListhttp://www.rxlist.com/cgi/generic3/diphenoxylate.htm
WikipediaDiphenoxylate
ATC CodesA07DA01
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelNot Available
MSDSshow(49.7 KB)
Interactions
Drug Interactions
Drug
AlvimopanIncreases levels by receptor binding competition. Discontinue opioid administration at least 7 days prior to administrating Alvimopan.
DonepezilPossible antagonism of action
GalantaminePossible antagonism of action
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