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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
1-(3-Cyano-3,3-diphenylpropyl)-4-phenyl-isonipecotic acid ethyl ester
2,2-Diphenyl-4-(4-carbethoxy-4-phenylpiperidino)butyronitrile
4-Ethoxycarbonyl-alpha,alpha,4-triphenyl-1-piperidinebutyronitrile
Difenossilato
Difenoxilato
Diphenoxylatum
Ethyl 1-(3-cyano-3,3-diphenylpropyl)-4-phenyl-4-piperidinecarboxylate
Ethyl 1-(3-cyano-3,3-diphenylpropyl)-4-phenylisonipecotate
External Identifiers
  • DEA No. 9170
  • R-1132
Approved Prescription ProductsNot Available
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International BrandsNot Available
Brand mixtures
NameLabellerIngredients
Diphenoxylate HCl and Atropine SulfateStat Rx USA
Diphenoxylate Hydrochloride and Atropine SulfateRoxane Laboratories, Inc
Direct RxDIRECT RX
LomotilG.D. Searle LLC Division of Pfizer Inc
Salts
Name/CASStructureProperties
Diphenoxylate Hydrochloride
Thumb
  • InChI Key: SHTAFWKOISOCBI-UHFFFAOYSA-N
  • Monoisotopic Mass: 488.223056017
  • Average Mass: 489.048
DBSALT000809
Categories
UNII73312P173G
CAS number915-30-0
WeightAverage: 452.5873
Monoisotopic: 452.246378278
Chemical FormulaC30H32N2O2
InChI KeyInChIKey=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
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.
Related Articles
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 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 )
Pharmacoeconomics
ManufacturersNot Available
Packagers
Dosage forms
FormRouteStrength
Solutionoral
Tabletoral
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
Spectra
Spectrum TypeDescriptionSplash Key
MSMass Spectrum (Electron Ionization)splash10-0002-2390000000-0d133bb29f340639db02View in MoNA
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 ReferencesNot Available
External Links
ATC CodesA07DA01
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelNot Available
MSDSDownload (49.7 KB)
Interactions
Drug Interactions
Drug
AzelastineDiphenoxylate may increase the central nervous system depressant (CNS depressant) activities of Azelastine.
BaclofenThe risk or severity of adverse effects can be increased when Baclofen is combined with Diphenoxylate.
BrimonidineBrimonidine may increase the central nervous system depressant (CNS depressant) activities of Diphenoxylate.
Cimetropium BromideDiphenoxylate may increase the anticholinergic activities of Cimetropium Bromide.
EluxadolineDiphenoxylate may increase the activities of Eluxadoline.
EthanolDiphenoxylate may increase the central nervous system depressant (CNS depressant) activities of Ethanol.
Ipratropium bromideIpratropium bromide may increase the anticholinergic activities of Diphenoxylate.
LorazepamThe risk or severity of adverse effects can be increased when Lorazepam is combined with Diphenoxylate.
MorphineThe risk or severity of adverse effects can be increased when Diphenoxylate is combined with Morphine.
ParoxetineThe risk or severity of adverse effects can be increased when Diphenoxylate is combined with Paroxetine.
ProcyclidineThe risk or severity of adverse effects can be increased when Procyclidine is combined with Diphenoxylate.
RamosetronDiphenoxylate may increase the activities of Ramosetron.
TacrineThe therapeutic efficacy of Diphenoxylate can be decreased when used in combination with Tacrine.
TrichlormethiazideThe serum concentration of Trichlormethiazide can be increased when it is combined with Diphenoxylate.
Food Interactions
  • Avoid alcohol.
  • Take with food.

Targets

Kind
Protein
Organism
Human
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. Agonist binding to the receptor induces coupling to an inactive GDP-bound heterotrimeric G-protein complex and subsequent exchange of GDP for GTP in the G-protein alpha subunit leading to dissociati...
Gene Name:
OPRM1
Uniprot ID:
P35372
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. [PubMed:11752352 ]
  2. Baker DE: Loperamide: a pharmacological review. Rev Gastroenterol Disord. 2007;7 Suppl 3:S11-8. [PubMed:18192961 ]
  3. Corazziari E: Role of opioid ligands in the irritable bowel syndrome. Can J Gastroenterol. 1999 Mar;13 Suppl A:71A-75A. [PubMed:10202212 ]
  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:8583364 ]
  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:8386327 ]
Kind
Protein
Organism
Human
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 nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Signaling leads to the inhibition of adenylate cyclase activity. Inhibits neurot...
Gene Name:
OPRD1
Uniprot ID:
P41143
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. [PubMed:8583364 ]
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Drug created on June 13, 2005 07:24 / Updated on April 15, 2014 11:41