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Identification
NameDifenoxin
Accession NumberDB01501
TypeSmall Molecule
GroupsApproved, Illicit
DescriptionDifenoxin 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.
Structure
Thumb
Synonyms
1-(3-Cyano-3,3-diphenylpropyl)-4-phenylisonipecotic acid
Difenoxin
Difenoxina
Difenoxinum
Diphenoxilic acid
Diphenoxin
Diphenoxylic acid
External Identifiers
  • McN-JR 15403-11
  • R-15403
Approved Prescription ProductsNot Available
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International Brands
NameCompany
LyspafenJanssen
Brand mixturesNot Available
Salts
Name/CASStructureProperties
Difenoxin hydrochloride
35607-36-4
Thumb
  • InChI Key: VMIZTXDGZPTKIK-UHFFFAOYSA-N
  • Monoisotopic Mass: 460.191755889
  • Average Mass: 460.995
DBSALT000047
Categories
UNII3ZZ5BJ9F2Q
CAS number28782-42-5
WeightAverage: 424.5341
Monoisotopic: 424.21507815
Chemical FormulaC28H28N2O2
InChI KeyUFIVBRCCIRTJTN-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
Pharmacology
IndicationMotofen(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.
Structured Indications Not Available
PharmacodynamicsDifenoxin 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 actionDifenoxin 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].
Related Articles
AbsorptionA high percentage of Motofen(R) is absorbed, and absorption occurs rapidly. Peak plasma concentrations are achieved within 40-60 minutes. [Lexicomp, 2013]
Volume of distributionNot Available
Protein bindingNot Available
Metabolism

Metabolism occurs by hydroxylation to form an inactive metabolite. [Lexicomp, 2013]

Route of eliminationBoth the drug and its metabolites are excreted, mainly as conjugates, in urine and feces. [Lexicomp, 2012]
Half lifeThe elimination half life was calculated to be 7.24 hours. The appearance half life was calculated to be 0.82h. [3]
ClearanceNot Available
ToxicityNot Available
Affected organismsNot Available
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
Interactions
Drug Interactions
DrugInteractionDrug group
1,1,1,2 TetrafluoroethaneThe risk or severity of adverse effects can be increased when Difenoxin is combined with 1,1,1,2 Tetrafluoroethane.Investigational
7-NitroindazoleThe risk or severity of adverse effects can be increased when 7-Nitroindazole is combined with Difenoxin.Experimental
AcepromazineThe risk or severity of adverse effects can be increased when Acepromazine is combined with Difenoxin.Approved, Vet Approved
AceprometazineThe risk or severity of adverse effects can be increased when Aceprometazine is combined with Difenoxin.Approved
adipiplonThe risk or severity of adverse effects can be increased when adipiplon is combined with Difenoxin.Investigational
AgomelatineThe risk or severity of adverse effects can be increased when Agomelatine is combined with Difenoxin.Approved, Investigational
AlfaxaloneThe risk or severity of adverse effects can be increased when Alfaxalone is combined with Difenoxin.Vet Approved
AlfentanilThe risk or severity of adverse effects can be increased when Alfentanil is combined with Difenoxin.Approved, Illicit
AlphacetylmethadolThe risk or severity of adverse effects can be increased when Alphacetylmethadol is combined with Difenoxin.Experimental, Illicit
AlprazolamThe risk or severity of adverse effects can be increased when Alprazolam is combined with Difenoxin.Approved, Illicit, Investigational
AmisulprideThe risk or severity of adverse effects can be increased when Amisulpride is combined with Difenoxin.Approved, Investigational
AmitriptylineThe risk or severity of adverse effects can be increased when Amitriptyline is combined with Difenoxin.Approved
AmobarbitalThe risk or severity of adverse effects can be increased when Amobarbital is combined with Difenoxin.Approved, Illicit
AmoxapineThe risk or severity of adverse effects can be increased when Amoxapine is combined with Difenoxin.Approved
AmperozideThe risk or severity of adverse effects can be increased when Amperozide is combined with Difenoxin.Experimental
AripiprazoleThe risk or severity of adverse effects can be increased when Aripiprazole is combined with Difenoxin.Approved, Investigational
ArticaineThe risk or severity of adverse effects can be increased when Articaine is combined with Difenoxin.Approved
AsenapineThe risk or severity of adverse effects can be increased when Asenapine is combined with Difenoxin.Approved
AzaperoneThe risk or severity of adverse effects can be increased when Azaperone is combined with Difenoxin.Vet Approved
AzelastineDifenoxin may increase the central nervous system depressant (CNS depressant) activities of Azelastine.Approved
AzelastineThe risk or severity of adverse effects can be increased when Azelastine is combined with Difenoxin.Approved
BaclofenThe risk or severity of adverse effects can be increased when Baclofen is combined with Difenoxin.Approved
BarbitalThe risk or severity of adverse effects can be increased when Barbital is combined with Difenoxin.Illicit
BenperidolThe risk or severity of adverse effects can be increased when Difenoxin is combined with Benperidol.Investigational
BenzocaineThe risk or severity of adverse effects can be increased when Benzocaine is combined with Difenoxin.Approved
Benzyl alcoholThe risk or severity of adverse effects can be increased when Benzyl alcohol is combined with Difenoxin.Approved
BrexpiprazoleThe risk or severity of adverse effects can be increased when Difenoxin is combined with Brexpiprazole.Approved
BrimonidineThe risk or severity of adverse effects can be increased when Brimonidine is combined with Difenoxin.Approved
BrimonidineBrimonidine may increase the central nervous system depressant (CNS depressant) activities of Difenoxin.Approved
BromazepamThe risk or severity of adverse effects can be increased when Bromazepam is combined with Difenoxin.Approved, Illicit
BrompheniramineThe risk or severity of adverse effects can be increased when Brompheniramine is combined with Difenoxin.Approved
BrotizolamThe risk or severity of adverse effects can be increased when Brotizolam is combined with Difenoxin.Approved, Withdrawn
BupivacaineThe risk or severity of adverse effects can be increased when Bupivacaine is combined with Difenoxin.Approved, Investigational
BuprenorphineDifenoxin may increase the central nervous system depressant (CNS depressant) activities of Buprenorphine.Approved, Illicit, Investigational, Vet Approved
BuspironeThe risk or severity of adverse effects can be increased when Buspirone is combined with Difenoxin.Approved, Investigational
ButabarbitalThe risk or severity of adverse effects can be increased when Butabarbital is combined with Difenoxin.Approved, Illicit
ButacaineThe risk or severity of adverse effects can be increased when Butacaine is combined with Difenoxin.Vet Approved
ButalbitalThe risk or severity of adverse effects can be increased when Butalbital is combined with Difenoxin.Approved, Illicit
ButambenThe risk or severity of adverse effects can be increased when Butamben is combined with Difenoxin.Approved
ButethalThe risk or severity of adverse effects can be increased when Butethal is combined with Difenoxin.Approved, Illicit
ButorphanolThe risk or severity of adverse effects can be increased when Butorphanol is combined with Difenoxin.Approved, Illicit, Vet Approved
CarbamazepineThe risk or severity of adverse effects can be increased when Carbamazepine is combined with Difenoxin.Approved, Investigational
CarbinoxamineThe risk or severity of adverse effects can be increased when Carbinoxamine is combined with Difenoxin.Approved
CarfentanilThe risk or severity of adverse effects can be increased when Carfentanil is combined with Difenoxin.Illicit, Vet Approved
CarisoprodolThe risk or severity of adverse effects can be increased when Carisoprodol is combined with Difenoxin.Approved
CetirizineThe risk or severity of adverse effects can be increased when Cetirizine is combined with Difenoxin.Approved
Chloral hydrateThe risk or severity of adverse effects can be increased when Chloral hydrate is combined with Difenoxin.Approved, Illicit, Vet Approved
ChlordiazepoxideThe risk or severity of adverse effects can be increased when Chlordiazepoxide is combined with Difenoxin.Approved, Illicit
ChlormezanoneThe risk or severity of adverse effects can be increased when Chlormezanone is combined with Difenoxin.Approved, Withdrawn
ChloroprocaineThe risk or severity of adverse effects can be increased when Chloroprocaine is combined with Difenoxin.Approved
ChlorphenamineThe risk or severity of adverse effects can be increased when Chlorphenamine is combined with Difenoxin.Approved
ChlorpromazineThe risk or severity of adverse effects can be increased when Chlorpromazine is combined with Difenoxin.Approved, Vet Approved
ChlorprothixeneThe risk or severity of adverse effects can be increased when Chlorprothixene is combined with Difenoxin.Approved, Withdrawn
ChlorzoxazoneThe risk or severity of adverse effects can be increased when Chlorzoxazone is combined with Difenoxin.Approved
CinchocaineThe risk or severity of adverse effects can be increased when Cinchocaine is combined with Difenoxin.Approved, Vet Approved
CitalopramThe risk or severity of adverse effects can be increased when Difenoxin is combined with Citalopram.Approved
ClemastineThe risk or severity of adverse effects can be increased when Clemastine is combined with Difenoxin.Approved
ClidiniumThe risk or severity of adverse effects can be increased when Clidinium is combined with Difenoxin.Approved
ClobazamThe risk or severity of adverse effects can be increased when Clobazam is combined with Difenoxin.Approved, Illicit
clomethiazoleThe risk or severity of adverse effects can be increased when clomethiazole is combined with Difenoxin.Investigational
ClomipramineThe risk or severity of adverse effects can be increased when Clomipramine is combined with Difenoxin.Approved, Vet Approved
ClonazepamThe risk or severity of adverse effects can be increased when Clonazepam is combined with Difenoxin.Approved, Illicit
ClonidineThe risk or severity of adverse effects can be increased when Clonidine is combined with Difenoxin.Approved
ClorazepateThe risk or severity of adverse effects can be increased when Clorazepate is combined with Difenoxin.Approved, Illicit
ClozapineThe risk or severity of adverse effects can be increased when Clozapine is combined with Difenoxin.Approved
CocaineThe risk or severity of adverse effects can be increased when Cocaine is combined with Difenoxin.Approved, Illicit
CodeineThe risk or severity of adverse effects can be increased when Codeine is combined with Difenoxin.Approved, Illicit
CyclizineThe risk or severity of adverse effects can be increased when Cyclizine is combined with Difenoxin.Approved
CyclobenzaprineThe risk or severity of adverse effects can be increased when Cyclobenzaprine is combined with Difenoxin.Approved
CyproheptadineThe risk or severity of adverse effects can be increased when Cyproheptadine is combined with Difenoxin.Approved
DantroleneThe risk or severity of adverse effects can be increased when Dantrolene is combined with Difenoxin.Approved
DapiprazoleThe risk or severity of adverse effects can be increased when Dapiprazole is combined with Difenoxin.Approved
DapoxetineThe risk or severity of adverse effects can be increased when Difenoxin is combined with Dapoxetine.Investigational
deramciclaneThe risk or severity of adverse effects can be increased when deramciclane is combined with Difenoxin.Investigational
DesfluraneThe risk or severity of adverse effects can be increased when Desflurane is combined with Difenoxin.Approved
DesipramineThe risk or severity of adverse effects can be increased when Desipramine is combined with Difenoxin.Approved
DesloratadineThe risk or severity of adverse effects can be increased when Desloratadine is combined with Difenoxin.Approved, Investigational
DesvenlafaxineThe risk or severity of adverse effects can be increased when Difenoxin is combined with Desvenlafaxine.Approved
DetomidineThe risk or severity of adverse effects can be increased when Detomidine is combined with Difenoxin.Vet Approved
DexbrompheniramineThe risk or severity of adverse effects can be increased when Dexbrompheniramine is combined with Difenoxin.Approved
DexmedetomidineThe risk or severity of adverse effects can be increased when Dexmedetomidine is combined with Difenoxin.Approved, Vet Approved
DextromoramideThe risk or severity of adverse effects can be increased when Dextromoramide is combined with Difenoxin.Experimental, Illicit
DextropropoxypheneThe risk or severity of adverse effects can be increased when Dextropropoxyphene is combined with Difenoxin.Approved, Illicit, Withdrawn
DezocineThe risk or severity of adverse effects can be increased when Dezocine is combined with Difenoxin.Approved
DiazepamThe risk or severity of adverse effects can be increased when Diazepam is combined with Difenoxin.Approved, Illicit, Vet Approved
DihydrocodeineThe risk or severity of adverse effects can be increased when Dihydrocodeine is combined with Difenoxin.Approved, Illicit
DihydroetorphineThe risk or severity of adverse effects can be increased when Dihydroetorphine is combined with Difenoxin.Experimental, Illicit
DihydromorphineThe risk or severity of adverse effects can be increased when Dihydromorphine is combined with Difenoxin.Experimental, Illicit
DimenhydrinateThe risk or severity of adverse effects can be increased when Dimenhydrinate is combined with Difenoxin.Approved
DiphenhydramineThe risk or severity of adverse effects can be increased when Diphenhydramine is combined with Difenoxin.Approved
DiphenoxylateThe risk or severity of adverse effects can be increased when Diphenoxylate is combined with Difenoxin.Approved, Illicit
DoramectinThe risk or severity of adverse effects can be increased when Doramectin is combined with Difenoxin.Vet Approved
DoxepinThe risk or severity of adverse effects can be increased when Doxepin is combined with Difenoxin.Approved
DoxylamineDoxylamine may increase the central nervous system depressant (CNS depressant) activities of Difenoxin.Approved, Vet Approved
DPDPEThe risk or severity of adverse effects can be increased when DPDPE is combined with Difenoxin.Investigational
DronabinolDronabinol may increase the central nervous system depressant (CNS depressant) activities of Difenoxin.Approved, Illicit
DroperidolDroperidol may increase the central nervous system depressant (CNS depressant) activities of Difenoxin.Approved, Vet Approved
DrotebanolThe risk or severity of adverse effects can be increased when Drotebanol is combined with Difenoxin.Experimental, Illicit
DuloxetineThe risk or severity of adverse effects can be increased when Difenoxin is combined with Duloxetine.Approved
DyclonineThe risk or severity of adverse effects can be increased when Dyclonine is combined with Difenoxin.Approved
EcgonineThe risk or severity of adverse effects can be increased when Ecgonine is combined with Difenoxin.Experimental, Illicit
ECGONINE METHYL ESTERThe risk or severity of adverse effects can be increased when ECGONINE METHYL ESTER is combined with Difenoxin.Experimental
EcopipamThe risk or severity of adverse effects can be increased when Difenoxin is combined with Ecopipam.Investigational
EfavirenzThe risk or severity of adverse effects can be increased when Efavirenz is combined with Difenoxin.Approved, Investigational
EnfluraneThe risk or severity of adverse effects can be increased when Enflurane is combined with Difenoxin.Approved, Vet Approved
EntacaponeThe risk or severity of adverse effects can be increased when Entacapone is combined with Difenoxin.Approved, Investigational
EscitalopramThe risk or severity of adverse effects can be increased when Difenoxin is combined with Escitalopram.Approved, Investigational
EstazolamThe risk or severity of adverse effects can be increased when Estazolam is combined with Difenoxin.Approved, Illicit
EszopicloneThe risk or severity of adverse effects can be increased when Eszopiclone is combined with Difenoxin.Approved
EthanolDifenoxin may increase the central nervous system depressant (CNS depressant) activities of Ethanol.Approved
EthchlorvynolThe risk or severity of adverse effects can be increased when Ethchlorvynol is combined with Difenoxin.Approved, Illicit, Withdrawn
EthosuximideThe risk or severity of adverse effects can be increased when Ethosuximide is combined with Difenoxin.Approved
EthotoinThe risk or severity of adverse effects can be increased when Ethotoin is combined with Difenoxin.Approved
Ethyl carbamateThe risk or severity of adverse effects can be increased when Ethyl carbamate is combined with Difenoxin.Withdrawn
Ethyl loflazepateThe risk or severity of adverse effects can be increased when Ethyl loflazepate is combined with Difenoxin.Approved, Illicit
EthylmorphineThe risk or severity of adverse effects can be increased when Ethylmorphine is combined with Difenoxin.Approved, Illicit
EtidocaineThe risk or severity of adverse effects can be increased when Etidocaine is combined with Difenoxin.Approved
EtifoxineThe risk or severity of adverse effects can be increased when Etifoxine is combined with Difenoxin.Withdrawn
EtizolamThe risk or severity of adverse effects can be increased when Etizolam is combined with Difenoxin.Approved
EtomidateThe risk or severity of adverse effects can be increased when Etomidate is combined with Difenoxin.Approved
EtoperidoneThe risk or severity of adverse effects can be increased when Difenoxin is combined with Etoperidone.Approved
EtorphineThe risk or severity of adverse effects can be increased when Etorphine is combined with Difenoxin.Illicit, Vet Approved
EzogabineThe risk or severity of adverse effects can be increased when Difenoxin is combined with Ezogabine.Approved
FelbamateThe risk or severity of adverse effects can be increased when Felbamate is combined with Difenoxin.Approved
FencamfamineThe risk or severity of adverse effects can be increased when Fencamfamine is combined with Difenoxin.Approved, Illicit, Withdrawn
FentanylThe risk or severity of adverse effects can be increased when Fentanyl is combined with Difenoxin.Approved, Illicit, Investigational, Vet Approved
FexofenadineThe risk or severity of adverse effects can be increased when Fexofenadine is combined with Difenoxin.Approved
FlibanserinThe risk or severity of adverse effects can be increased when Difenoxin is combined with Flibanserin.Approved
FludiazepamThe risk or severity of adverse effects can be increased when Fludiazepam is combined with Difenoxin.Approved, Illicit
FlunarizineThe risk or severity of adverse effects can be increased when Difenoxin is combined with Flunarizine.Approved
FlunitrazepamThe risk or severity of adverse effects can be increased when Flunitrazepam is combined with Difenoxin.Approved, Illicit
FluoxetineThe risk or severity of adverse effects can be increased when Difenoxin is combined with Fluoxetine.Approved, Vet Approved
FlupentixolThe risk or severity of adverse effects can be increased when Flupentixol is combined with Difenoxin.Approved, Withdrawn
FluphenazineThe risk or severity of adverse effects can be increased when Fluphenazine is combined with Difenoxin.Approved
FlurazepamThe risk or severity of adverse effects can be increased when Flurazepam is combined with Difenoxin.Approved, Illicit
FluspirileneThe risk or severity of adverse effects can be increased when Fluspirilene is combined with Difenoxin.Approved
Fluticasone PropionateThe risk or severity of adverse effects can be increased when Fluticasone Propionate is combined with Difenoxin.Approved
FluvoxamineThe risk or severity of adverse effects can be increased when Fluvoxamine is combined with Difenoxin.Approved, Investigational
FosphenytoinThe risk or severity of adverse effects can be increased when Fosphenytoin is combined with Difenoxin.Approved
FospropofolThe risk or severity of adverse effects can be increased when Fospropofol is combined with Difenoxin.Approved, Illicit
GabapentinThe risk or severity of adverse effects can be increased when Gabapentin is combined with Difenoxin.Approved, Investigational
gabapentin enacarbilThe risk or severity of adverse effects can be increased when Difenoxin is combined with gabapentin enacarbil.Approved
Gamma Hydroxybutyric AcidThe risk or severity of adverse effects can be increased when Gamma Hydroxybutyric Acid is combined with Difenoxin.Approved, Illicit
GepironeThe risk or severity of adverse effects can be increased when Difenoxin is combined with Gepirone.Investigational
GlutethimideThe risk or severity of adverse effects can be increased when Glutethimide is combined with Difenoxin.Approved, Illicit
GuanfacineThe risk or severity of adverse effects can be increased when Guanfacine is combined with Difenoxin.Approved, Investigational
HalazepamThe risk or severity of adverse effects can be increased when Halazepam is combined with Difenoxin.Approved, Illicit, Withdrawn
HaloperidolThe risk or severity of adverse effects can be increased when Haloperidol is combined with Difenoxin.Approved
HalothaneThe risk or severity of adverse effects can be increased when Halothane is combined with Difenoxin.Approved, Vet Approved
HeroinThe risk or severity of adverse effects can be increased when Heroin is combined with Difenoxin.Approved, Illicit
HexobarbitalThe risk or severity of adverse effects can be increased when Hexobarbital is combined with Difenoxin.Approved
HydrocodoneDifenoxin may increase the central nervous system depressant (CNS depressant) activities of Hydrocodone.Approved, Illicit
HydromorphoneThe risk or severity of adverse effects can be increased when Hydromorphone is combined with Difenoxin.Approved, Illicit
HydroxyzineHydroxyzine may increase the central nervous system depressant (CNS depressant) activities of Difenoxin.Approved
IloperidoneThe risk or severity of adverse effects can be increased when Difenoxin is combined with Iloperidone.Approved
ImipramineThe risk or severity of adverse effects can be increased when Imipramine is combined with Difenoxin.Approved
IndalpineThe risk or severity of adverse effects can be increased when Difenoxin is combined with Indalpine.Investigational, Withdrawn
IsofluraneThe risk or severity of adverse effects can be increased when Isoflurane is combined with Difenoxin.Approved, Vet Approved
KetamineThe risk or severity of adverse effects can be increased when Ketamine is combined with Difenoxin.Approved, Vet Approved
KetazolamThe risk or severity of adverse effects can be increased when Ketazolam is combined with Difenoxin.Approved
KetobemidoneThe risk or severity of adverse effects can be increased when Ketobemidone is combined with Difenoxin.Approved
LamotrigineThe risk or severity of adverse effects can be increased when Lamotrigine is combined with Difenoxin.Approved, Investigational
LevetiracetamThe risk or severity of adverse effects can be increased when Levetiracetam is combined with Difenoxin.Approved, Investigational
LevobupivacaineThe risk or severity of adverse effects can be increased when Levobupivacaine is combined with Difenoxin.Approved
LevocabastineThe risk or severity of adverse effects can be increased when Difenoxin is combined with Levocabastine.Approved
LevocetirizineThe risk or severity of adverse effects can be increased when Difenoxin is combined with Levocetirizine.Approved
LevodopaThe risk or severity of adverse effects can be increased when Levodopa is combined with Difenoxin.Approved
Levomethadyl AcetateThe risk or severity of adverse effects can be increased when Levomethadyl Acetate is combined with Difenoxin.Approved
LevomilnacipranThe risk or severity of adverse effects can be increased when Difenoxin is combined with Levomilnacipran.Approved
LevorphanolThe risk or severity of adverse effects can be increased when Levorphanol is combined with Difenoxin.Approved
LidocaineThe risk or severity of adverse effects can be increased when Lidocaine is combined with Difenoxin.Approved, Vet Approved
LithiumThe risk or severity of adverse effects can be increased when Lithium is combined with Difenoxin.Approved
LofentanilThe risk or severity of adverse effects can be increased when Lofentanil is combined with Difenoxin.Illicit
LoratadineThe risk or severity of adverse effects can be increased when Loratadine is combined with Difenoxin.Approved
LorazepamThe risk or severity of adverse effects can be increased when Lorazepam is combined with Difenoxin.Approved
LoxapineThe risk or severity of adverse effects can be increased when Loxapine is combined with Difenoxin.Approved
Lu AA21004The risk or severity of adverse effects can be increased when Lu AA21004 is combined with Difenoxin.Investigational
LurasidoneThe risk or severity of adverse effects can be increased when Lurasidone is combined with Difenoxin.Approved
Magnesium SulfateMagnesium Sulfate may increase the central nervous system depressant (CNS depressant) activities of Difenoxin.Approved, Vet Approved
MaprotilineThe risk or severity of adverse effects can be increased when Maprotiline is combined with Difenoxin.Approved
MeclizineThe risk or severity of adverse effects can be increased when Meclizine is combined with Difenoxin.Approved
MedetomidineThe risk or severity of adverse effects can be increased when Medetomidine is combined with Difenoxin.Vet Approved
MelatoninThe risk or severity of adverse effects can be increased when Melatonin is combined with Difenoxin.Approved, Nutraceutical, Vet Approved
MelperoneThe risk or severity of adverse effects can be increased when Melperone is combined with Difenoxin.Approved
MepivacaineThe risk or severity of adverse effects can be increased when Mepivacaine is combined with Difenoxin.Approved, Vet Approved
MeprobamateThe risk or severity of adverse effects can be increased when Meprobamate is combined with Difenoxin.Approved, Illicit
MesoridazineThe risk or severity of adverse effects can be increased when Mesoridazine is combined with Difenoxin.Approved
MetaxaloneThe risk or severity of adverse effects can be increased when Metaxalone is combined with Difenoxin.Approved
MethadoneThe risk or severity of adverse effects can be increased when Methadone is combined with Difenoxin.Approved
Methadyl AcetateThe risk or severity of adverse effects can be increased when Methadyl Acetate is combined with Difenoxin.Approved, Illicit
MethapyrileneThe risk or severity of adverse effects can be increased when Methapyrilene is combined with Difenoxin.Withdrawn
MethaqualoneThe risk or severity of adverse effects can be increased when Methaqualone is combined with Difenoxin.Illicit, Withdrawn
MethocarbamolThe risk or severity of adverse effects can be increased when Methocarbamol is combined with Difenoxin.Approved, Vet Approved
MethohexitalThe risk or severity of adverse effects can be increased when Methohexital is combined with Difenoxin.Approved
MethotrimeprazineDifenoxin may increase the central nervous system depressant (CNS depressant) activities of Methotrimeprazine.Approved
MethoxyfluraneThe risk or severity of adverse effects can be increased when Methoxyflurane is combined with Difenoxin.Approved, Vet Approved
MethsuximideThe risk or severity of adverse effects can be increased when Difenoxin is combined with Methsuximide.Approved
MethylphenobarbitalThe risk or severity of adverse effects can be increased when Methylphenobarbital is combined with Difenoxin.Approved
MetyrosineDifenoxin may increase the sedative activities of Metyrosine.Approved
MidazolamThe risk or severity of adverse effects can be increased when Midazolam is combined with Difenoxin.Approved, Illicit
MilnacipranThe risk or severity of adverse effects can be increased when Difenoxin is combined with Milnacipran.Approved
MinocyclineMinocycline may increase the central nervous system depressant (CNS depressant) activities of Difenoxin.Approved, Investigational
MirtazapineDifenoxin may increase the central nervous system depressant (CNS depressant) activities of Mirtazapine.Approved
MolindoneThe risk or severity of adverse effects can be increased when Molindone is combined with Difenoxin.Approved
MorphineThe risk or severity of adverse effects can be increased when Morphine is combined with Difenoxin.Approved, Investigational
NabiloneNabilone may increase the central nervous system depressant (CNS depressant) activities of Difenoxin.Approved, Investigational
NalbuphineThe risk or severity of adverse effects can be increased when Nalbuphine is combined with Difenoxin.Approved
NefazodoneThe risk or severity of adverse effects can be increased when Difenoxin is combined with Nefazodone.Approved, Withdrawn
NitrazepamThe risk or severity of adverse effects can be increased when Nitrazepam is combined with Difenoxin.Approved
Nitrous oxideThe risk or severity of adverse effects can be increased when Nitrous oxide is combined with Difenoxin.Approved, Vet Approved
NormethadoneThe risk or severity of adverse effects can be increased when Normethadone is combined with Difenoxin.Approved, Illicit
NortriptylineThe risk or severity of adverse effects can be increased when Nortriptyline is combined with Difenoxin.Approved
OlanzapineThe risk or severity of adverse effects can be increased when Olanzapine is combined with Difenoxin.Approved, Investigational
OlopatadineThe risk or severity of adverse effects can be increased when Olopatadine is combined with Difenoxin.Approved
OndansetronThe risk or severity of adverse effects can be increased when Ondansetron is combined with Difenoxin.Approved
OpiumThe risk or severity of adverse effects can be increased when Opium is combined with Difenoxin.Approved, Illicit
OrphenadrineDifenoxin may increase the central nervous system depressant (CNS depressant) activities of Orphenadrine.Approved
OsanetantThe risk or severity of adverse effects can be increased when Osanetant is combined with Difenoxin.Investigational
OxazepamThe risk or severity of adverse effects can be increased when Oxazepam is combined with Difenoxin.Approved
OxetacaineThe risk or severity of adverse effects can be increased when Difenoxin is combined with Oxetacaine.Investigational
OxprenololThe risk or severity of adverse effects can be increased when Oxprenolol is combined with Difenoxin.Approved
OxybuprocaineThe risk or severity of adverse effects can be increased when Oxybuprocaine is combined with Difenoxin.Approved
OxycodoneThe risk or severity of adverse effects can be increased when Oxycodone is combined with Difenoxin.Approved, Illicit, Investigational
OxymorphoneThe risk or severity of adverse effects can be increased when Oxymorphone is combined with Difenoxin.Approved, Investigational, Vet Approved
PaliperidoneThe risk or severity of adverse effects can be increased when Paliperidone is combined with Difenoxin.Approved
ParaldehydeDifenoxin may increase the central nervous system depressant (CNS depressant) activities of Paraldehyde.Approved
ParoxetineThe risk or severity of adverse effects can be increased when Difenoxin is combined with Paroxetine.Approved, Investigational
PentazocineThe risk or severity of adverse effects can be increased when Pentazocine is combined with Difenoxin.Approved, Vet Approved
PentobarbitalThe risk or severity of adverse effects can be increased when Pentobarbital is combined with Difenoxin.Approved, Vet Approved
PerampanelPerampanel may increase the central nervous system depressant (CNS depressant) activities of Difenoxin.Approved
PerazineThe risk or severity of adverse effects can be increased when Difenoxin is combined with Perazine.Investigational
PerospironeThe risk or severity of adverse effects can be increased when Perospirone is combined with Difenoxin.Approved
PerphenazineThe risk or severity of adverse effects can be increased when Perphenazine is combined with Difenoxin.Approved
PethidineThe risk or severity of adverse effects can be increased when Pethidine is combined with Difenoxin.Approved
PhenobarbitalThe risk or severity of adverse effects can be increased when Phenobarbital is combined with Difenoxin.Approved
PhenoxyethanolThe risk or severity of adverse effects can be increased when Phenoxyethanol is combined with Difenoxin.Approved
PhenytoinThe risk or severity of adverse effects can be increased when Phenytoin is combined with Difenoxin.Approved, Vet Approved
PimozideThe risk or severity of adverse effects can be increased when Pimozide is combined with Difenoxin.Approved
PipamperoneThe risk or severity of adverse effects can be increased when Pipamperone is combined with Difenoxin.Approved
PipotiazineThe risk or severity of adverse effects can be increased when Difenoxin is combined with Pipotiazine.Approved
PiritramideThe risk or severity of adverse effects can be increased when Difenoxin is combined with Piritramide.Investigational
PizotifenThe risk or severity of adverse effects can be increased when Difenoxin is combined with Pizotifen.Approved
PomalidomideThe risk or severity of adverse effects can be increased when Difenoxin is combined with Pomalidomide.Approved
PramipexoleDifenoxin may increase the sedative activities of Pramipexole.Approved, Investigational
PramocaineThe risk or severity of adverse effects can be increased when Pramocaine is combined with Difenoxin.Approved
PrazepamThe risk or severity of adverse effects can be increased when Prazepam is combined with Difenoxin.Approved, Illicit
PregabalinThe risk or severity of adverse effects can be increased when Pregabalin is combined with Difenoxin.Approved, Illicit, Investigational
PregnanoloneThe risk or severity of adverse effects can be increased when Difenoxin is combined with Pregnanolone.Investigational
PrilocaineThe risk or severity of adverse effects can be increased when Prilocaine is combined with Difenoxin.Approved
PrimidoneThe risk or severity of adverse effects can be increased when Primidone is combined with Difenoxin.Approved, Vet Approved
ProcaineThe risk or severity of adverse effects can be increased when Procaine is combined with Difenoxin.Approved, Investigational, Vet Approved
ProchlorperazineThe risk or severity of adverse effects can be increased when Prochlorperazine is combined with Difenoxin.Approved, Vet Approved
PromazineThe risk or severity of adverse effects can be increased when Promazine is combined with Difenoxin.Approved, Vet Approved
PromethazineThe risk or severity of adverse effects can be increased when Promethazine is combined with Difenoxin.Approved
ProparacaineThe risk or severity of adverse effects can be increased when Proparacaine is combined with Difenoxin.Approved, Vet Approved
PropofolThe risk or severity of adverse effects can be increased when Propofol is combined with Difenoxin.Approved, Investigational, Vet Approved
PropoxycaineThe risk or severity of adverse effects can be increased when Propoxycaine is combined with Difenoxin.Approved
ProtriptylineThe risk or severity of adverse effects can be increased when Protriptyline is combined with Difenoxin.Approved
PSD502The risk or severity of adverse effects can be increased when PSD502 is combined with Difenoxin.Investigational
QuazepamThe risk or severity of adverse effects can be increased when Quazepam is combined with Difenoxin.Approved, Illicit
QuetiapineThe risk or severity of adverse effects can be increased when Quetiapine is combined with Difenoxin.Approved
RacloprideThe risk or severity of adverse effects can be increased when Difenoxin is combined with Raclopride.Investigational
RamelteonThe risk or severity of adverse effects can be increased when Ramelteon is combined with Difenoxin.Approved, Investigational
RemifentanilThe risk or severity of adverse effects can be increased when Remifentanil is combined with Difenoxin.Approved
RemoxiprideThe risk or severity of adverse effects can be increased when Remoxipride is combined with Difenoxin.Approved, Withdrawn
ReserpineThe risk or severity of adverse effects can be increased when Reserpine is combined with Difenoxin.Approved
RisperidoneThe risk or severity of adverse effects can be increased when Risperidone is combined with Difenoxin.Approved, Investigational
RitanserinThe risk or severity of adverse effects can be increased when Difenoxin is combined with Ritanserin.Investigational
RomifidineThe risk or severity of adverse effects can be increased when Romifidine is combined with Difenoxin.Vet Approved
RopiniroleDifenoxin may increase the sedative activities of Ropinirole.Approved, Investigational
RopivacaineThe risk or severity of adverse effects can be increased when Ropivacaine is combined with Difenoxin.Approved
RotigotineDifenoxin may increase the sedative activities of Rotigotine.Approved
RufinamideThe risk or severity of adverse effects can be increased when Rufinamide is combined with Difenoxin.Approved
S-EthylisothioureaThe risk or severity of adverse effects can be increased when S-Ethylisothiourea is combined with Difenoxin.Experimental
Sage 547The risk or severity of adverse effects can be increased when Difenoxin is combined with Sage 547.Investigational
ScopolamineThe risk or severity of adverse effects can be increased when Scopolamine is combined with Difenoxin.Approved
SecobarbitalThe risk or severity of adverse effects can be increased when Secobarbital is combined with Difenoxin.Approved, Vet Approved
SertindoleThe risk or severity of adverse effects can be increased when Sertindole is combined with Difenoxin.Approved, Withdrawn
SertralineThe risk or severity of adverse effects can be increased when Difenoxin is combined with Sertraline.Approved
SevofluraneThe risk or severity of adverse effects can be increased when Sevoflurane is combined with Difenoxin.Approved, Vet Approved
Sodium oxybateSodium oxybate may increase the central nervous system depressant (CNS depressant) activities of Difenoxin.Approved
StiripentolThe risk or severity of adverse effects can be increased when Difenoxin is combined with Stiripentol.Approved
SufentanilThe risk or severity of adverse effects can be increased when Sufentanil is combined with Difenoxin.Approved, Investigational
SulpirideThe risk or severity of adverse effects can be increased when Sulpiride is combined with Difenoxin.Approved
SuvorexantDifenoxin may increase the central nervous system depressant (CNS depressant) activities of Suvorexant.Approved
TandospironeThe risk or severity of adverse effects can be increased when Difenoxin is combined with Tandospirone.Investigational
TapentadolTapentadol may increase the central nervous system depressant (CNS depressant) activities of Difenoxin.Approved
TasimelteonThe risk or severity of adverse effects can be increased when Difenoxin is combined with Tasimelteon.Approved
TemazepamThe risk or severity of adverse effects can be increased when Temazepam is combined with Difenoxin.Approved
TetrabenazineThe risk or severity of adverse effects can be increased when Difenoxin is combined with Tetrabenazine.Approved
TetracaineThe risk or severity of adverse effects can be increased when Tetracaine is combined with Difenoxin.Approved, Vet Approved
TetrodotoxinThe risk or severity of adverse effects can be increased when Tetrodotoxin is combined with Difenoxin.Investigational
ThalidomideDifenoxin may increase the central nervous system depressant (CNS depressant) activities of Thalidomide.Approved, Investigational, Withdrawn
ThiamylalThe risk or severity of adverse effects can be increased when Thiamylal is combined with Difenoxin.Approved, Vet Approved
ThiopentalThe risk or severity of adverse effects can be increased when Thiopental is combined with Difenoxin.Approved, Vet Approved
ThioridazineThe risk or severity of adverse effects can be increased when Thioridazine is combined with Difenoxin.Approved
ThiothixeneThe risk or severity of adverse effects can be increased when Thiothixene is combined with Difenoxin.Approved
TiagabineThe risk or severity of adverse effects can be increased when Tiagabine is combined with Difenoxin.Approved
TiaprideThe risk or severity of adverse effects can be increased when Difenoxin is combined with Tiapride.Investigational
TiletamineThe risk or severity of adverse effects can be increased when Tiletamine is combined with Difenoxin.Vet Approved
TizanidineThe risk or severity of adverse effects can be increased when Tizanidine is combined with Difenoxin.Approved
TolcaponeThe risk or severity of adverse effects can be increased when Tolcapone is combined with Difenoxin.Approved, Withdrawn
TopiramateThe risk or severity of adverse effects can be increased when Topiramate is combined with Difenoxin.Approved
TramadolThe risk or severity of adverse effects can be increased when Tramadol is combined with Difenoxin.Approved, Investigational
Trans-2-PhenylcyclopropylamineThe risk or severity of adverse effects can be increased when Trans-2-Phenylcyclopropylamine is combined with Difenoxin.Experimental
TranylcypromineThe risk or severity of adverse effects can be increased when Tranylcypromine is combined with Difenoxin.Approved
TrazodoneThe risk or severity of adverse effects can be increased when Trazodone is combined with Difenoxin.Approved, Investigational
TriazolamThe risk or severity of adverse effects can be increased when Triazolam is combined with Difenoxin.Approved
TrifluoperazineThe risk or severity of adverse effects can be increased when Trifluoperazine is combined with Difenoxin.Approved
TriflupromazineThe risk or severity of adverse effects can be increased when Triflupromazine is combined with Difenoxin.Approved, Vet Approved
TrimipramineThe risk or severity of adverse effects can be increased when Trimipramine is combined with Difenoxin.Approved
TriprolidineThe risk or severity of adverse effects can be increased when Triprolidine is combined with Difenoxin.Approved
Uc1010The risk or severity of adverse effects can be increased when Difenoxin is combined with Uc1010.Investigational
Valproic AcidThe risk or severity of adverse effects can be increased when Valproic Acid is combined with Difenoxin.Approved, Investigational
VenlafaxineThe risk or severity of adverse effects can be increased when Difenoxin is combined with Venlafaxine.Approved
VigabatrinThe risk or severity of adverse effects can be increased when Vigabatrin is combined with Difenoxin.Approved
VortioxetineThe risk or severity of adverse effects can be increased when Vortioxetine is combined with Difenoxin.Approved
XylazineThe risk or severity of adverse effects can be increased when Xylazine is combined with Difenoxin.Vet Approved
ZaleplonThe risk or severity of adverse effects can be increased when Zaleplon is combined with Difenoxin.Approved, Illicit, Investigational
ZiconotideThe risk or severity of adverse effects can be increased when Difenoxin is combined with Ziconotide.Approved
ZimelidineThe risk or severity of adverse effects can be increased when Difenoxin is combined with Zimelidine.Withdrawn
ZiprasidoneThe risk or severity of adverse effects can be increased when Ziprasidone is combined with Difenoxin.Approved
ZolazepamThe risk or severity of adverse effects can be increased when Zolazepam is combined with Difenoxin.Vet Approved
ZolpidemDifenoxin may increase the central nervous system depressant (CNS depressant) activities of Zolpidem.Approved
ZonisamideThe risk or severity of adverse effects can be increased when Zonisamide is combined with Difenoxin.Approved, Investigational
ZopicloneThe risk or severity of adverse effects can be increased when Zopiclone is combined with Difenoxin.Approved
ZotepineThe risk or severity of adverse effects can be increased when Zotepine is combined with Difenoxin.Approved
ZuclopenthixolThe risk or severity of adverse effects can be increased when Zuclopenthixol is combined with Difenoxin.Approved, Investigational
Food Interactions
  • Ethanol use may increase CNS depression.
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
  1. 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 ]
  2. 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. [PubMed:6675727 ]
  3. 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. [PubMed:3682841 ]
External Links
ATC CodesA07DA04
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelNot Available
MSDSNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9182
Blood Brain Barrier+0.8984
Caco-2 permeable+0.507
P-glycoprotein substrateSubstrate0.6311
P-glycoprotein inhibitor INon-inhibitor0.7353
P-glycoprotein inhibitor IIInhibitor0.5519
Renal organic cation transporterInhibitor0.6229
CYP450 2C9 substrateNon-substrate0.8171
CYP450 2D6 substrateNon-substrate0.6612
CYP450 3A4 substrateNon-substrate0.6411
CYP450 1A2 substrateNon-inhibitor0.8832
CYP450 2C9 inhibitorNon-inhibitor0.8628
CYP450 2D6 inhibitorNon-inhibitor0.6599
CYP450 2C19 inhibitorNon-inhibitor0.8411
CYP450 3A4 inhibitorNon-inhibitor0.6724
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9199
Ames testNon AMES toxic0.8242
CarcinogenicityNon-carcinogens0.9211
BiodegradationNot ready biodegradable0.9849
Rat acute toxicity3.4236 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.827
hERG inhibition (predictor II)Non-inhibitor0.6311
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
ManufacturersNot Available
Packagers
Dosage formsNot Available
PricesNot Available
PatentsNot Available
Properties
StateSolid
Experimental PropertiesNot Available
Predicted Properties
PropertyValueSource
Water Solubility0.00208 mg/mLALOGPS
logP4.39ALOGPS
logP2.65ChemAxon
logS-5.3ALOGPS
pKa (Strongest Acidic)3.38ChemAxon
pKa (Strongest Basic)9.41ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area64.33 Å2ChemAxon
Rotatable Bond Count7ChemAxon
Refractivity137.24 m3·mol-1ChemAxon
Polarizability47.56 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Download (7.02 KB)
SpectraNot Available
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
  • Azacycle
  • Organoheterocyclic compound
  • Nitrile
  • Carbonitrile
  • Monocarboxylic acid or derivatives
  • Carboxylic acid
  • Carboxylic acid derivative
  • Hydrocarbon derivative
  • Organooxygen compound
  • Organonitrogen compound
  • Carbonyl group
  • Amine
  • Aromatic heteromonocyclic compound
Molecular FrameworkAromatic heteromonocyclic compounds
External Descriptors
Comments
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Drug created on July 31, 2007 07:10 / Updated on August 17, 2016 12:23