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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
Structure for Diphenoxylate (DB01081)
- 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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Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Used as adjunct in combination to manage Diarrhea Combination Product in combination with: Atropine (DB00572) •••••••••••• - Contraindications & Blackbox Warnings
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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.
Target Actions Organism AMu-type opioid receptor agonistHumans UDelta-type opioid receptor agonistHumans - 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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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
Pathway Category Diphenoxylate Action Pathway Drug 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.
Drug Interaction Integrate drug-drug
interactions in your software1,2-Benzodiazepine The risk or severity of adverse effects can be increased when Diphenoxylate is combined with 1,2-Benzodiazepine. Acetazolamide The risk or severity of CNS depression can be increased when Acetazolamide is combined with Diphenoxylate. Acetophenazine The risk or severity of hypotension and CNS depression can be increased when Acetophenazine is combined with Diphenoxylate. Aclidinium The risk or severity of adverse effects can be increased when Aclidinium is combined with Diphenoxylate. Agomelatine The risk or severity of CNS depression can be increased when Diphenoxylate is combined with Agomelatine. - Food Interactions
- Avoid alcohol.
- Take with food.
Products
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Ingredient UNII CAS InChI Key Diphenoxylate hydrochloride W24OD7YW48 3810-80-8 SHTAFWKOISOCBI-UHFFFAOYSA-N - Product Images
- Mixture Products
Name Ingredients Dosage Route Labeller Marketing Start Marketing End Region Image BEAMOTIL TABLET Diphenoxylate hydrochloride (2.5 mg) + Atropine sulfate anhydrous (0.025 mg) Tablet Oral DUOPHARMA MANUFACTURING (BANGI) SDN. BHD. 2020-09-08 Not applicable Malaysia 
BEAMOTIL TABLETS Diphenoxylate hydrochloride (2.5 mg) + Atropine sulfate anhydrous (0.025 mg) Tablet, film coated Oral BEACONS PHARMACEUTICALS PTE. LTD. 1991-06-01 Not applicable Singapore 
DHAMOTIL TABLET Diphenoxylate hydrochloride (2.5 mg) + Atropine sulfate anhydrous (0.025 mg) Tablet, film coated Oral TEVA PHARMACEUTICAL INVESTMENTS SINGAPORE PTE. LTD. 1991-01-29 Not applicable Singapore Diphenoxylate Hcl and Atropine Sulfate Diphenoxylate hydrochloride (2.5 mg/1) + Atropine sulfate (0.025 mg/1) Tablet Oral Stat Rx USA 1979-10-29 Not applicable US 
Diphenoxylate Hydrochloride and Atropine Sulfate Diphenoxylate hydrochloride (2.5 mg/1) + Atropine sulfate (0.025 mg/1) Tablet Oral Cardinal Health 1960-09-15 2017-08-31 US
Categories
- ATC Codes
- A07DA01 — Diphenoxylate
- Drug Categories
- Alimentary Tract and Metabolism
- Analgesics
- Antidiarrheals
- Antidiarrheals, Intestinal Antiinflammatory/antiinfective Agents
- Antipropulsives
- Central Nervous System Agents
- Central Nervous System Depressants
- Gastrointestinal Agents
- Isonipecotic Acids
- Opioids
- Peripheral Nervous System Agents
- Piperidines
- Sensory System Agents
- Serotonergic Drugs Shown to Increase Risk of Serotonin Syndrome
- 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
- External Links
- Human Metabolome Database
- HMDB0015213
- KEGG Drug
- D00301
- KEGG Compound
- C07872
- PubChem Compound
- 13505
- PubChem Substance
- 46507130
- ChemSpider
- 12919
- BindingDB
- 50401672
- 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
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package Phase Status Purpose Conditions Count Start Date Why Stopped 100+ additional columns Unlock 175K+ rows when you subscribe.View sample data3 Completed Diagnostic Lymphoma 1 somestatus stop reason just information to hide 2 Completed Treatment Breast 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 v7 1 somestatus stop reason just information to hide
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
Form Route Strength Tablet, film coated Oral 0.025 mg Tablet, film coated Oral Solution Oral Tablet Oral Liquid Oral Tablet Tablet 2.5 mg/0.025mg Tablet Oral 0.025 mg Syrup Oral 0.025 mg/5ml - Prices
Unit description Cost Unit Lomotil 2.5-0.025 mg/5ml Liquid 60ml Bottle 30.86USD bottle Lomotil 2.5-0.025 mg tablet 1.4USD tablet Lomotil tablet 1.12USD tablet DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.- Patents
- Not Available
Properties
- State
- Solid
- Experimental Properties
Property Value Source melting point (°C) 220.5-222 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. water solubility 800 mg/L (at 25 °C) MERCK INDEX (1996) logP 6.3 Not Available - Predicted Properties
Property Value Source Water Solubility 0.00146 mg/mL ALOGPS logP 5.74 ALOGPS logP 5.88 Chemaxon logS -5.5 ALOGPS pKa (Strongest Basic) 8.5 Chemaxon Physiological Charge 1 Chemaxon Hydrogen Acceptor Count 3 Chemaxon Hydrogen Donor Count 0 Chemaxon Polar Surface Area 53.33 Å2 Chemaxon Rotatable Bond Count 9 Chemaxon Refractivity 146.76 m3·mol-1 Chemaxon Polarizability 51.58 Å3 Chemaxon Number of Rings 4 Chemaxon Bioavailability 1 Chemaxon Rule of Five No Chemaxon Ghose Filter No Chemaxon Veber's Rule No Chemaxon MDDR-like Rule Yes Chemaxon - 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 inhibitor Inhibitor 0.6701 CYP450 2D6 inhibitor Inhibitor 0.6461 CYP450 2C19 inhibitor Inhibitor 0.51 CYP450 3A4 inhibitor 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
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
- Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 221.2785426 predictedDarkChem Lite v0.1.0 [M-H]- 205.49118 predictedDeepCCS 1.0 (2019) [M+H]+ 222.0756426 predictedDarkChem Lite v0.1.0 [M+H]+ 207.88675 predictedDeepCCS 1.0 (2019) [M+Na]+ 221.5339426 predictedDarkChem Lite v0.1.0 [M+Na]+ 213.92134 predictedDeepCCS 1.0 (2019)
Targets
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Use our structured and evidence-based datasets to unlock newinsights and accelerate drug research.
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- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Agonist
- General Function
- Receptor for endogenous opioids such as beta-endorphin and endomorphin (PubMed:10529478, PubMed:12589820, PubMed:7891175, PubMed:7905839, PubMed:7957926, PubMed:9689128). Receptor for natural and synthetic opioids including morphine, heroin, DAMGO, fentanyl, etorphine, buprenorphin and methadone (PubMed:10529478, PubMed:10836142, PubMed:12589820, PubMed:19300905, PubMed:7891175, PubMed:7905839, PubMed:7957926, PubMed:9689128). Also activated by enkephalin peptides, such as Met-enkephalin or Met-enkephalin-Arg-Phe, with higher affinity for Met-enkephalin-Arg-Phe (By similarity). 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 dissociation of the G-protein complex with the free GTP-bound G-protein alpha and the G-protein beta-gamma dimer activating downstream cellular effectors (PubMed:7905839). The agonist- and cell type-specific activity is predominantly coupled to pertussis toxin-sensitive G(i) and G(o) G alpha proteins, GNAI1, GNAI2, GNAI3 and GNAO1 isoforms Alpha-1 and Alpha-2, and to a lesser extent to pertussis toxin-insensitive G alpha proteins GNAZ and GNA15 (PubMed:12068084). They mediate an array of downstream cellular responses, including inhibition of adenylate cyclase activity and both N-type and L-type calcium channels, activation of inward rectifying potassium channels, mitogen-activated protein kinase (MAPK), phospholipase C (PLC), phosphoinositide/protein kinase (PKC), phosphoinositide 3-kinase (PI3K) and regulation of NF-kappa-B (By similarity). Also couples to adenylate cyclase stimulatory G alpha proteins (By similarity). The selective temporal coupling to G-proteins and subsequent signaling can be regulated by RGSZ proteins, such as RGS9, RGS17 and RGS4 (By similarity). Phosphorylation by members of the GPRK subfamily of Ser/Thr protein kinases and association with beta-arrestins is involved in short-term receptor desensitization (By similarity). Beta-arrestins associate with the GPRK-phosphorylated receptor and uncouple it from the G-protein thus terminating signal transduction (By similarity). The phosphorylated receptor is internalized through endocytosis via clathrin-coated pits which involves beta-arrestins (By similarity). The activation of the ERK pathway occurs either in a G-protein-dependent or a beta-arrestin-dependent manner and is regulated by agonist-specific receptor phosphorylation (By similarity). Acts as a class A G-protein coupled receptor (GPCR) which dissociates from beta-arrestin at or near the plasma membrane and undergoes rapid recycling (By similarity). Receptor down-regulation pathways are varying with the agonist and occur dependent or independent of G-protein coupling (By similarity). Endogenous ligands induce rapid desensitization, endocytosis and recycling (By similarity). Heterooligomerization with other GPCRs can modulate agonist binding, signaling and trafficking properties (By similarity)
- Specific Function
- Beta-endorphin receptor activity
- Gene Name
- OPRM1
- Uniprot ID
- P35372
- Uniprot Name
- Mu-type opioid receptor
- Molecular Weight
- 44778.855 Da
References
- Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
- Baker DE: Loperamide: a pharmacological review. Rev Gastroenterol Disord. 2007;7 Suppl 3:S11-8. [Article]
- Corazziari E: Role of opioid ligands in the irritable bowel syndrome. Can J Gastroenterol. 1999 Mar;13 Suppl A:71A-75A. [Article]
- 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]
- 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]
- Zhou Y, Zhang Y, Zhao D, Yu X, Shen X, Zhou Y, Wang S, Qiu Y, Chen Y, Zhu F: TTD: Therapeutic Target Database describing target druggability information. Nucleic Acids Res. 2024 Jan 5;52(D1):D1465-D1477. doi: 10.1093/nar/gkad751. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Agonist
- General Function
- G-protein coupled receptor that functions as a 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 neurotransmitter release by reducing calcium ion currents and increasing potassium ion conductance. Plays a role in the perception of pain and in opiate-mediated analgesia. Plays a role in developing analgesic tolerance to morphine
- Specific Function
- G protein-coupled enkephalin receptor activity
- Gene Name
- OPRD1
- Uniprot ID
- P41143
- Uniprot Name
- Delta-type opioid receptor
- Molecular Weight
- 40368.235 Da
References
- 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 September 15, 2024 04:51