Loperamide

Identification

Summary

Loperamide is a long acting antidiarrheal used to control nonspecific diarrhea and chronic diarrhea caused by inflammatory bowel disease, or gastroenteritis.

Brand Names
Diamode, Imodium, Imodium Multi-symptom Relief
Generic Name
Loperamide
DrugBank Accession Number
DB00836
Background

Loperamide is an anti-diarrheal agent that is available as an over-the-counter product for treating diarrhea.7 The drug was first synthesized in 1969 and used medically in 1976.1 It is a highly lipophilic synthetic phenylpiperidine opioid that works by binding to mu-opioid receptors on intestinal muscles to decrease intestinal motility and electrolyte loss.1 Loperamide has a chemical structure that is similar to diphenoxylate and haloperidol;2 however, loperamide works on mu (μ)-opioid receptors to mediate its pharmacological actions.1

Type
Small Molecule
Groups
Approved
Structure
Weight
Average: 477.038
Monoisotopic: 476.223056017
Chemical Formula
C29H33ClN2O2
Synonyms
  • Loperamid
  • Loperamida
  • Lopéramide
  • Loperamide
  • Loperamidum
External IDs
  • PJ 185
  • R 18553

Pharmacology

Indication

Loperamide is indicated for the relief of diarrhea, including Travelers’ Diarrhea.7 As an off-label use, it is often used to manage chemotherapy-related diarrhea.1

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Symptomatic treatment ofDiarrhea••••••••••••
Symptomatic treatment ofTraveler's diarrhea••• •••
Contraindications & Blackbox Warnings
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Pharmacodynamics

Loperamide is an anti-diarrheal agent that provides symptomatic relief of diarrhea.8 It decreases peristalsis and fluid secretion in the gastrointestinal tract, delays colonic transit time, and increases the absorption of fluids and electrolytes from the gastrointestinal tract.2,1,5 Loperamide also increases rectal tone,1 reduces daily fecal volume, and increases the viscosity and bulk density of feces.8 It also increases the tone of the anal sphincter, thereby reducing incontinence and urgency.3,8 The onset of action is about one hour and the duration of action can be up to three days.3

While loperamide is a potent mu-opioid receptor agonist,3 it does not mediate significant analgesic activity at therapeutic and supratherapeutic doses.2,3 However, at high doses of loperamide, inhibition of P-glycoprotein-mediated drug efflux may allow loperamide to cross the blood-brain barrier, where loperamide can exert central opioid effects and toxicity.1

At very high plasma concentrations, loperamide can interfere with cardiac conduction.4 Because loperamide inhibits the Na+-gated cardiac channels 1 and ether-a-go-go–related gene potassium channels,4 the drug can prolong the QRS complex and the QTc interval, which can lead to ventricular dysrhythmias, monomorphic and polymorphic ventricular tachycardia, torsade de pointes, ventricular fibrillation, Brugada syndrome, cardiac arrest, and death.1

Mechanism of action

Enteric neurons synthesize and release endogenous opioid peptides and other neurotransmitters, such as acetylcholine and substance P. Endogenous opioids bind to opioid receptors expressed on these neurons to regulate gastrointestinal signalling, motility, and balance of fluids and electrolytes.5

Loperamide acts on the mu (μ)-opioid receptor expressed on the circular and longitudinal intestinal muscle.1 Receptor binding leads to the recruitment of G-protein receptor kinases and the activation of downstream molecular cascades that inhibit enteric nerve activity.5 By inhibiting the excitability of enteric neurons, loperamide suppresses neurotransmitter release, pre-synaptic and post-synaptic inhibition of transmission of excitatory and inhibitory motor pathways, and secretomotor pathways.5 Loperamide inhibits the release of acetylcholine and prostaglandins,8 thereby reducing propulsive peristalsis and increasing intestinal transit time.3,8 Loperamide stimulates the intestinal absorption of water and electrolytes by inhibiting calmodulin.3 Loperamide can bind to and hyperpolarize submucosal secretomotor neurons, promoting dry, hard stools.5

TargetActionsOrganism
AMu-type opioid receptor
agonist
Humans
UDelta-type opioid receptor
agonist
Humans
UKappa-type opioid receptor
agonist
Humans
UPro-opiomelanocortin
modulator
Humans
NVoltage-dependent P/Q-type calcium channel subunit alpha-1A
blocker
Humans
NVoltage-gated inwardly rectifying potassium channel KCNH2
blocker
Humans
UCalmodulin
inhibitor
Humans
Absorption

Loperamide is well absorbed from the gastrointestinal tract; however, it undergoes extensive first-pass metabolism to form metabolites that are excreted in the bile. Therefore, little loperamide actually reaches the systemic circulation.3 The drug bioavailability is less than 1%.1

Following oral administration of a 2 mg capsule of loperamide, plasma concentrations of unchanged drug were below 2 ng/mL. Plasma loperamide concentrations are highest approximately five hours after administration of an oral capsule of loperamide and 2.5 hours after the liquid formulation of the drug.8

Volume of distribution

Loperamide has a large volume of distribution.1 Although highly lipophilic, loperamide does not cross the blood-brain barrier 2 and generally acts peripherally.3

Protein binding

Based on literature information, the plasma protein binding of loperamide is about 95%.8

Metabolism

Loperamide is extensively metabolized. The primary metabolic pathway is oxidative N-demethylation mediated by CYP2C8 and CYP3A4, to form N-demethyl loperamide. CYP2B6 and CYP2D6 play a minor role in loperamide N-demethylation.8 Metabolites of loperamide are pharmacologically inactive.4

Hover over products below to view reaction partners

Route of elimination

Loperamide and its metabolites in the systemic circulation undergo biliary excretion.4 Excretion of the unchanged loperamide and its metabolites mainly occurs through the feces.8 Only 1% of an absorbed dose excreted unchanged in the urine.4

Half-life

The apparent elimination half-life of loperamide is 10.8 hours with a range of 9.1 to 14.4 hours.8

Clearance

Not Available

Adverse Effects
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Toxicity

Oral LD50 is 185 mg/kg in rats.6

Due to its actions on opioid receptors, loperamide has been misused and abused to self-manage opioid withdrawal symptoms and to induce euphoria.1,4 However, loperamide is associated with a risk of experiencing a range of adverse effects, often life-threatening, if taken for non-therapeutic reasons or at doses higher than the recommended dose.8 Loperamide overdose can lead to a range of cardiac and non-cardiac effects. Chronic ingestion of doses ranging from 70 mg to 1600 mg daily - which is four to 100 times the recommended dose - resulted in life-threatening cardiac adverse reactions, including QT/QTc and QRS interval prolongation, Torsades de Pointes, Brugada syndrome and other ventricular arrhythmias, syncope, cardiac arrest, and death. These cases included instances of loperamide misuse and abuse. In case of cardiac effects, it is recommended that loperamide is discontinued and therapies to manage and prevent cardiac arrhythmias are initiated.8 Cases of loperamide overdose may cause opioid toxic effects including CNS depression (e.g. altered mental status, stupor, coordination disorders, somnolence, miosis, muscular hypertonia, respiratory depression), hypotension, urinary retention, and paralytic ileus.8 Naloxone may reverse the opioid-related toxicity, including CNS and respiratory depression, and hypotension, associated with loperamide overdosage.8

Pathways
Not Available
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.
DrugInteraction
AbametapirThe serum concentration of Loperamide can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Loperamide can be increased when combined with Abatacept.
AbemaciclibThe serum concentration of Abemaciclib can be increased when it is combined with Loperamide.
AbirateroneThe metabolism of Loperamide can be decreased when combined with Abiraterone.
AbrocitinibThe excretion of Loperamide can be decreased when combined with Abrocitinib.
Food Interactions
Not Available

Products

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Product Ingredients
IngredientUNIICASInChI Key
Loperamide hydrochloride77TI35393C34552-83-5PGYPOBZJRVSMDS-UHFFFAOYSA-N
Product Images
International/Other Brands
Dimor (Nordic Drugs) / Fortasec (Esteve) / Kaopectate II (Chattem, Inc.) / Lopedium (Sandoz) / Lopedium express (Sandoz) / Lopex (Orion) / Maalox Anti-Diarrheal (Novartis International AG) / Pepto Diarrhea Control (Procter & Gamble )
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
ImodiumCapsule2 mg/1OralMcNeil Consumer Healthcare2008-02-26Not applicableUS flag
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Loperamide HydrochlorideCapsule2 mg/1OralNcs Health Care Of Ky, Inc Dba Vangard Labs2012-10-12Not applicableUS flag
Loperamide HydrochlorideCapsule2 mg/1OralAdvagen Pharma Ltd2023-01-26Not applicableUS flag
Loperamide HydrochlorideSolution2 mg/10mLOralRoxane Laboratories1992-04-302011-07-18US flag
Loperamide HydrochlorideCapsule2 mg/1OralAphena Pharma Solutions - Tennessee, LLC2012-10-12Not applicableUS flag
Loperamide HydrochlorideCapsule2 mg/1OralStat Rx USA1993-05-01Not applicableUS flag
Over the Counter Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
7 Select Anti DiarrhealTablet, film coated2 mg/1Oral7-Eleven2014-08-052021-02-28US flag
7 Select Anti DiarrhealSolution1 mg/7.5mLOral7-Eleven2018-08-072021-04-30US flag
A DTablet, film coated2 mg/1OralWestern Family Foods2003-04-102017-08-12US flag
A DTablet, film coated2 mg/1OralWestern Family Foods2003-02-252017-08-29US flag
Alti-loperamide - 2mg CapletTablet2 mgOralAltimed Pharma Inc.1995-12-311997-08-14Canada flag
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
Anti Diarrheal and Anti GasLoperamide hydrochloride (2 mg/1) + Dimethicone (125 mg/1)TabletOralCVS PHARMACY2019-08-06Not applicableUS flag
Anti Diarrheal and Anti GasLoperamide hydrochloride (2 mg/1) + Dimethicone (125 mg/1)TabletOralWalgreen Company2018-10-10Not applicableUS flag
Anti Diarrheal Anti GasLoperamide hydrochloride (2 mg/1) + Dimethicone (125 mg/1)TabletOralAmerisource Bergen2018-12-28Not applicableUS flag
Anti Diarrheal Anti GasLoperamide hydrochloride (2 mg/1) + Dimethicone (125 mg/1)TabletOralRite Aid Corporation2019-01-03Not applicableUS flag
Anti Diarrheal Anti GasLoperamide hydrochloride (2 mg/1) + Dimethicone (125 mg/1)TabletOralKroger Company2019-04-24Not applicableUS flag
Unapproved/Other Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
Gadavyt Loperamide HClLoperamide hydrochloride (1 mg/5mL)LiquidOralGadal Laboratories, Inc.2013-05-01Not applicableUS flag
Meds on the GoLoperamide hydrochloride (2 mg/1) + Acetaminophen (500 mg/1) + Acetaminophen (325 mg/1) + Calcium carbonate (420 mg/1) + Dextromethorphan hydrobromide monohydrate (15 mg/1) + Guaifenesin (200 mg/1) + Ibuprofen (200 mg/1) + Phenylephrine hydrochloride (5 mg/1)KitOralDoc In The Box Llc2019-01-01Not applicableUS flag

Categories

ATC Codes
A07DA53 — Loperamide, combinationsA07DA03 — Loperamide
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as diphenylmethanes. These are compounds containing a diphenylmethane moiety, which consists of a methane wherein two hydrogen atoms are replaced by two phenyl groups.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
Diphenylmethanes
Direct Parent
Diphenylmethanes
Alternative Parents
Phenylpiperidines / Phenylacetamides / Aralkylamines / Chlorobenzenes / Aryl chlorides / N-acyl amines / Tertiary carboxylic acid amides / Tertiary alcohols / Trialkylamines / Amino acids and derivatives
show 6 more
Substituents
Alcohol / Amine / Amino acid or derivatives / Aralkylamine / Aromatic heteromonocyclic compound / Aryl chloride / Aryl halide / Azacycle / Carbonyl group / Carboxamide group
show 22 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
piperidines, tertiary alcohol, monocarboxylic acid amide, monochlorobenzenes (CHEBI:6532)
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
6X9OC3H4II
CAS number
53179-11-6
InChI Key
RDOIQAHITMMDAJ-UHFFFAOYSA-N
InChI
InChI=1S/C29H33ClN2O2/c1-31(2)27(33)29(24-9-5-3-6-10-24,25-11-7-4-8-12-25)19-22-32-20-17-28(34,18-21-32)23-13-15-26(30)16-14-23/h3-16,34H,17-22H2,1-2H3
IUPAC Name
4-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-N,N-dimethyl-2,2-diphenylbutanamide
SMILES
CN(C)C(=O)C(CCN1CCC(O)(CC1)C1=CC=C(Cl)C=C1)(C1=CC=CC=C1)C1=CC=CC=C1

References

Synthesis Reference

Tsutomu Awamura, Hisanobu Nishikawa, Toshio Inagi, "FILM PREPARATION CONTAINING LOPERAMIDE HYDROCHLORIDE." U.S. Patent US20110159058, issued June 30, 2011.

US20110159058
General References
  1. Sahi N, Nguyen R, Santos C: Loperamide . [Article]
  2. Baker DE: Loperamide: a pharmacological review. Rev Gastroenterol Disord. 2007;7 Suppl 3:S11-8. [Article]
  3. Regnard C, Twycross R, Mihalyo M, Wilcock A: Loperamide. J Pain Symptom Manage. 2011 Aug;42(2):319-23. doi: 10.1016/j.jpainsymman.2011.06.001. Epub 2011 Jun 23. [Article]
  4. Wu PE, Juurlink DN: Clinical Review: Loperamide Toxicity. Ann Emerg Med. 2017 Aug;70(2):245-252. doi: 10.1016/j.annemergmed.2017.04.008. Epub 2017 May 13. [Article]
  5. Pannemans J, Corsetti M: Opioid receptors in the GI tract: targets for treatment of both diarrhea and constipation in functional bowel disorders? Curr Opin Pharmacol. 2018 Dec;43:53-58. doi: 10.1016/j.coph.2018.08.008. Epub 2018 Sep 3. [Article]
  6. Thermo Fisher Scientific: Loperamide hydrochloride MSDS [Link]
  7. DailyMed Label: ANTI-DIARRHEAL (loperamide hcl) Oral Tablet [Link]
  8. FDA Discontinued Drug Products: IMODIUM (loperamide) Oral Tablets [Link]
Human Metabolome Database
HMDB0004999
KEGG Drug
D08144
KEGG Compound
C07080
PubChem Compound
3955
PubChem Substance
46504591
ChemSpider
3818
BindingDB
50017698
RxNav
6468
ChEBI
6532
ChEMBL
CHEMBL841
ZINC
ZINC000000537928
Therapeutic Targets Database
DAP000425
PharmGKB
PA450262
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
PDRhealth
PDRhealth Drug Page
Wikipedia
Loperamide

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
PhaseStatusPurposeConditionsCountStart DateWhy Stopped100+ additional columns
Not AvailableCompletedNot AvailableHealthy Volunteers (HV)1somestatusstop reasonjust information to hide
Not AvailableCompletedBasic ScienceIntestinal Transit1somestatusstop reasonjust information to hide
Not AvailableCompletedTreatmentFecal Incontinence1somestatusstop reasonjust information to hide
Not AvailableCompletedTreatmentLow Anterior Resection Syndrome1somestatusstop reasonjust information to hide
Not AvailableTerminatedTreatmentAcute Watery Diarrhea / Dysentery/Febrile Diarrhea1somestatusstop reasonjust information to hide

Pharmacoeconomics

Manufacturers
  • Mcneil consumer healthcare
  • Mcneil pediatrics
  • Janssen pharmaceutica products lp
Packagers
  • Advanced Pharmaceutical Services Inc.
  • AQ Pharmaceuticals Inc.
  • A-S Medication Solutions LLC
  • Cardinal Health
  • Chain Drug
  • Chattem Chemicals Inc.
  • Comprehensive Consultant Services Inc.
  • CVS Pharmacy
  • Dept Health Central Pharmacy
  • DHHS Program Support Center Supply Service Center
  • Direct Dispensing Inc.
  • Dispensing Solutions
  • Diversified Healthcare Services Inc.
  • Heartland Repack Services LLC
  • Janssen-Ortho Inc.
  • Lake Chemicals Pvt Ltd.
  • Lake Erie Medical and Surgical Supply
  • Liberty Pharmaceuticals
  • Major Pharmaceuticals
  • McNeil Laboratories
  • Medique Products
  • Medisca Inc.
  • Mylan
  • Novopharm Ltd.
  • Nucare Pharmaceuticals Inc.
  • Palmetto Pharmaceuticals Inc.
  • PCA LLC
  • PD-Rx Pharmaceuticals Inc.
  • Perrigo Co.
  • Pharmacia Inc.
  • Physicians Total Care Inc.
  • Preferred Pharmaceuticals Inc.
  • Prepackage Specialists
  • Prepak Systems Inc.
  • Qualitest
  • Redpharm Drug
  • Remedy Repack
  • Rugby Laboratories
  • Sandhills Packaging Inc.
  • Teva Pharmaceutical Industries Ltd.
  • Tya Pharmaceuticals
  • UDL Laboratories
  • Vangard Labs Inc.
Dosage Forms
FormRouteStrength
SuspensionOral20 mg
Tablet, film coatedOral
SolutionOral1 mg/5mL
Tablet, coatedOral2 mg/1
Solution / dropsOral
CapsuleOral2.00 MG
SuspensionOral40 mg
SyrupOral1 mg/5ml
SyrupOral
KitOral
SolutionOral.2 mg / mL
LiquidOral1 mg/5mL
CapsuleOral
CapsuleOral2 mg/1
Capsule, coatedOral2 mg
Solution / dropsOral0.2 %
TabletOral
TabletOral2.152 mg
Tablet, chewableOral
SolutionOral1 mg/7.5mL
Tablet, chewableOral2 mg/1
SolutionOral2 mg / 15 mL
CapsuleOral2 mg / cap
TabletOral2 mg / tab
SolutionOral0.2 mg
LiquidOral.2 mg / mL
Tablet, orally disintegratingOral2 mg
CapsuleOral
Tablet, effervescentOral2 mg
SolutionOral0.2 MG/ML
SolutionOral2 mg
SolutionOral2 MG/ML
Capsule, liquid filledOral2 mg/1
LiquidOral1 mg/7.5mL
SolutionOral2 mg/10mL
TabletOral2 mg/1
TabletOral
TabletOral2.00 mg
SyrupOral1.05 mg/5ml
Tablet, effervescentOral
Tablet, coatedOral2 mg
Tablet, film coatedOral2 mg/1
SolutionOral0.2 mg / mL
SuspensionOral1 mg/7.5mL
SyrupOral20 mg
CapsuleOral2 mg
TabletOral2.000 mg
Injection, powder, for solution400 MG
SolutionOral20 mg
TabletOral2 mg
Tablet, film coatedOral2 mg
Prices
Unit descriptionCostUnit
Loperamide hcl powder26.01USD g
Loperamide HCl 2 mg capsule0.64USD capsule
Imodium a-d 2 mg caplet0.49USD caplet
Imodium advanced caplet0.46USD caplet
Imodium ms relief caplet0.46USD caplet
Kaopectate 262 mg caplet0.37USD caplet
Loperamide 2 mg caplet0.37USD caplet
Qc anti-diarrheal adv caplet0.3USD caplet
Diamode 2 mg tablet0.28USD tablet
Kaopectate 240 mg softgel0.25USD softgel capsule
Anti-diarrheal 2 mg caplet0.18USD caplet
CVS Pharmacy anti-diarrheal 2 mg caplet0.14USD caplet
Kaopectate children's suspension0.02USD ml
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
CA2134611No2002-12-242014-10-28Canada flag
US6814978Yes2004-11-092022-02-26US flag
US6103260No2000-08-152017-07-17US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)220-228https://www.medisca.com/NDC_SPECS/MUS/0446/MSDS/0446.pdf
logP5.13https://www.medisca.com/NDC_SPECS/MUS/0446/MSDS/0446.pdf
Predicted Properties
PropertyValueSource
Water Solubility0.00086 mg/mLALOGPS
logP4.44ALOGPS
logP4.77Chemaxon
logS-5.7ALOGPS
pKa (Strongest Acidic)13.96Chemaxon
pKa (Strongest Basic)9.41Chemaxon
Physiological Charge1Chemaxon
Hydrogen Acceptor Count3Chemaxon
Hydrogen Donor Count1Chemaxon
Polar Surface Area43.78 Å2Chemaxon
Rotatable Bond Count7Chemaxon
Refractivity139.32 m3·mol-1Chemaxon
Polarizability52.59 Å3Chemaxon
Number of Rings4Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterNoChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleYesChemaxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.9878
Blood Brain Barrier+0.7709
Caco-2 permeable+0.5875
P-glycoprotein substrateSubstrate0.7476
P-glycoprotein inhibitor IInhibitor0.8277
P-glycoprotein inhibitor IIInhibitor0.8387
Renal organic cation transporterInhibitor0.5059
CYP450 2C9 substrateNon-substrate0.8057
CYP450 2D6 substrateNon-substrate0.5315
CYP450 3A4 substrateSubstrate0.7918
CYP450 1A2 substrateNon-inhibitor0.9045
CYP450 2C9 inhibitorNon-inhibitor0.9154
CYP450 2D6 inhibitorInhibitor0.8933
CYP450 2C19 inhibitorNon-inhibitor0.9026
CYP450 3A4 inhibitorNon-inhibitor0.8309
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9207
Ames testNon AMES toxic0.768
CarcinogenicityNon-carcinogens0.8564
BiodegradationNot ready biodegradable0.9953
Rat acute toxicity3.6560 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9461
hERG inhibition (predictor II)Inhibitor0.7639
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSsplash10-0pi0-5322900000-2bef1a5d1980c912f5c8
MS/MS Spectrum - Quattro_QQQ 10V, PositiveLC-MS/MSsplash10-004i-0000900000-673950710672b433271c
MS/MS Spectrum - Quattro_QQQ 25V, PositiveLC-MS/MSsplash10-014i-0090000000-4b7b347a8b8e9dca406c
MS/MS Spectrum - Quattro_QQQ 40V, PositiveLC-MS/MSsplash10-02t9-0090000000-31f15df976e23e73330a
LC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 10V, PositiveLC-MS/MSsplash10-004i-0000900000-d91d13c4e4665bd5fb5a
LC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 20V, PositiveLC-MS/MSsplash10-004i-0020900000-f1be3181a6918c985ffd
LC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 30V, PositiveLC-MS/MSsplash10-014i-0090000000-e5e41346303f41f65688
LC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 40V, PositiveLC-MS/MSsplash10-014i-0090000000-acd8b87c1338e5d0fe25
LC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 50V, PositiveLC-MS/MSsplash10-014i-0090000000-81b85f788d14641430fd
LC-MS/MS Spectrum - LC-ESI-IT (LC/MSD Trap XCT, Agilent Technologies) , PositiveLC-MS/MSsplash10-014i-0090000000-3ce1a89454d777268799
LC-MS/MS Spectrum - LC-ESI-IT (LC/MSD Trap XCT, Agilent Technologies) , PositiveLC-MS/MSsplash10-03di-0090000000-f101d63ad0bf8e5d2178
LC-MS/MS Spectrum - LC-ESI-QQ , positiveLC-MS/MSsplash10-004i-0000900000-d91d13c4e4665bd5fb5a
LC-MS/MS Spectrum - LC-ESI-QQ , positiveLC-MS/MSsplash10-004i-0020900000-f1be3181a6918c985ffd
LC-MS/MS Spectrum - LC-ESI-QQ , positiveLC-MS/MSsplash10-014i-0090000000-e5e41346303f41f65688
LC-MS/MS Spectrum - LC-ESI-QQ , positiveLC-MS/MSsplash10-014i-0090000000-acd8b87c1338e5d0fe25
LC-MS/MS Spectrum - LC-ESI-QQ , positiveLC-MS/MSsplash10-014i-0090000000-81b85f788d14641430fd
LC-MS/MS Spectrum - LC-ESI-IT , positiveLC-MS/MSsplash10-014i-0090000000-1a1a49f09397ad090e82
MS/MS Spectrum - , positiveLC-MS/MSsplash10-016r-0090600000-794ea6214c0cd97c73fa
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-016r-0090300000-e11942e343a28799a5ab
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-004i-0000900000-ea0e953dd81061c402bc
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-004i-1001900000-79bccf9c769e1419ee08
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-000i-2009700000-72af1603467f8a61f826
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-0560-9012600000-dfe04b5105cf8ead6527
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-002r-1549400000-13548081331d8701b39d
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-001i-9104000000-f564b6cbc7ec2f23e0fd
1H NMR Spectrum1D NMRNot Applicable
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
[1H,13C] 2D NMR Spectrum2D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-224.2118976
predicted
DarkChem Lite v0.1.0
[M-H]-201.8119
predicted
DeepCCS 1.0 (2019)
[M+H]+224.3830976
predicted
DarkChem Lite v0.1.0
[M+H]+204.17729
predicted
DeepCCS 1.0 (2019)
[M+Na]+223.6963976
predicted
DarkChem Lite v0.1.0
[M+Na]+210.6571
predicted
DeepCCS 1.0 (2019)

Targets

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Details
1. Mu-type opioid receptor
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
  1. DeHaven-Hudkins DL, Burgos LC, Cassel JA, Daubert JD, DeHaven RN, Mansson E, Nagasaka H, Yu G, Yaksh T: Loperamide (ADL 2-1294), an opioid antihyperalgesic agent with peripheral selectivity. J Pharmacol Exp Ther. 1999 Apr;289(1):494-502. [Article]
  2. Tan-No K, Niijima F, Nakagawasai O, Sato T, Satoh S, Tadano T: Development of tolerance to the inhibitory effect of loperamide on gastrointestinal transit in mice. Eur J Pharm Sci. 2003 Nov;20(3):357-63. [Article]
  3. Roge J, Baumer P, Berard H, Schwartz JC, Lecomte JM: The enkephalinase inhibitor, acetorphan, in acute diarrhoea. A double-blind, controlled clinical trial versus loperamide. Scand J Gastroenterol. 1993 Apr;28(4):352-4. [Article]
  4. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
  5. Giagnoni G, Casiraghi L, Senini R, Revel L, Parolaro D, Sala M, Gori E: Loperamide: evidence of interaction with mu and delta opioid receptors. Life Sci. 1983;33 Suppl 1:315-8. [Article]
  6. di Bosco AM, Grieco P, Diurno MV, Campiglia P, Novellino E, Mazzoni O: Binding site of loperamide: automated docking of loperamide in human mu- and delta-opioid receptors. Chem Biol Drug Des. 2008 Apr;71(4):328-35. doi: 10.1111/j.1747-0285.2008.00637.x. Epub 2008 Feb 12. [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
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
  2. Giagnoni G, Casiraghi L, Senini R, Revel L, Parolaro D, Sala M, Gori E: Loperamide: evidence of interaction with mu and delta opioid receptors. Life Sci. 1983;33 Suppl 1:315-8. [Article]
  3. di Bosco AM, Grieco P, Diurno MV, Campiglia P, Novellino E, Mazzoni O: Binding site of loperamide: automated docking of loperamide in human mu- and delta-opioid receptors. Chem Biol Drug Des. 2008 Apr;71(4):328-35. doi: 10.1111/j.1747-0285.2008.00637.x. Epub 2008 Feb 12. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Agonist
General Function
G-protein coupled opioid receptor that functions as a receptor for endogenous alpha-neoendorphins and dynorphins, but has low affinity for beta-endorphins. Also functions as a receptor for various synthetic opioids and for the psychoactive diterpene salvinorin A. 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. Plays a role in mediating reduced physical activity upon treatment with synthetic opioids. Plays a role in the regulation of salivation in response to synthetic opioids. May play a role in arousal and regulation of autonomic and neuroendocrine functions
Specific Function
dynorphin receptor activity
Gene Name
OPRK1
Uniprot ID
P41145
Uniprot Name
Kappa-type opioid receptor
Molecular Weight
42644.665 Da
References
  1. DeHaven-Hudkins DL, Burgos LC, Cassel JA, Daubert JD, DeHaven RN, Mansson E, Nagasaka H, Yu G, Yaksh T: Loperamide (ADL 2-1294), an opioid antihyperalgesic agent with peripheral selectivity. J Pharmacol Exp Ther. 1999 Apr;289(1):494-502. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Modulator
General Function
Stimulates the adrenal glands to release cortisol
Specific Function
G protein-coupled receptor binding
Gene Name
POMC
Uniprot ID
P01189
Uniprot Name
Pro-opiomelanocortin
Molecular Weight
29423.72 Da
References
  1. Nomura A, Iwasaki Y, Aoki Y, Yamamori E, Mutsuga N, Yoshida M, Asai M, Oiso Y, Saito H: Effects of loperamide and other opioid-related substances on the transcriptional regulation of the rat pro-opiomelanocortin gene in AtT20 cells. Neuroendocrinology. 2001 Aug;74(2):87-94. [Article]
  2. Auernhammer CJ, Stalla GK, Lange M, Pfeiffer A, Muller OA: Effects of loperamide on the human hypothalamo-pituitary-adrenal axis in vivo and in vitro. J Clin Endocrinol Metab. 1992 Aug;75(2):552-7. [Article]
  3. Ambrosi B, Bochicchio D, Ferrario R, Colombo P, Faglia G: Effects of the opiate agonist loperamide on pituitary-adrenal function in patients with suspected hypercortisolism. J Endocrinol Invest. 1989 Jan;12(1):31-5. [Article]
  4. Ambrosi B, Bochicchio D, Colombo P, Ferrario R, Faglia G: Loperamide modifies but does not block the corticotropin-releasing hormone-induced ACTH response in patients with Addison's disease. Horm Metab Res Suppl. 1987;16:74-5. [Article]
  5. Bochicchio D, Ambrosi B, Faglia G: Loperamide, an opiate analog, differently modifies the adrenocorticotropin responses to corticotropin-releasing hormone and lysine vasopressin in patients with Addison's disease. Neuroendocrinology. 1988 Dec;48(6):611-4. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Blocker
General Function
Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death. The isoform alpha-1A gives rise to P and/or Q-type calcium currents. P/Q-type calcium channels belong to the 'high-voltage activated' (HVA) group and are specifically blocked by the spider omega-agatoxin-IVA (AC P54282) (By similarity). They are however insensitive to dihydropyridines (DHP)
Specific Function
amyloid-beta binding
Gene Name
CACNA1A
Uniprot ID
O00555
Uniprot Name
Voltage-dependent P/Q-type calcium channel subunit alpha-1A
Molecular Weight
282561.605 Da
References
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [Article]
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [Article]
  3. Church J, Fletcher EJ, Abdel-Hamid K, MacDonald JF: Loperamide blocks high-voltage-activated calcium channels and N-methyl-D-aspartate-evoked responses in rat and mouse cultured hippocampal pyramidal neurons. Mol Pharmacol. 1994 Apr;45(4):747-57. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Blocker
General Function
Pore-forming (alpha) subunit of voltage-gated inwardly rectifying potassium channel (PubMed:10219239, PubMed:10753933, PubMed:10790218, PubMed:10837251, PubMed:11997281, PubMed:12063277, PubMed:18559421, PubMed:22314138, PubMed:22359612, PubMed:26363003, PubMed:27916661, PubMed:9230439, PubMed:9351446, PubMed:9765245). Channel properties are modulated by cAMP and subunit assembly (PubMed:10837251). Characterized by unusual gating kinetics by producing relatively small outward currents during membrane depolarization and large inward currents during subsequent repolarization which reflect a rapid inactivation during depolarization and quick recovery from inactivation but slow deactivation (closing) during repolarization (PubMed:10219239, PubMed:10753933, PubMed:10790218, PubMed:10837251, PubMed:11997281, PubMed:12063277, PubMed:18559421, PubMed:22314138, PubMed:22359612, PubMed:26363003, PubMed:27916661, PubMed:9230439, PubMed:9351446, PubMed:9765245). Channel properties are modulated by cAMP and subunit assembly (PubMed:10837251). Forms a stable complex with KCNE1 or KCNE2, and that this heteromultimerization regulates inward rectifier potassium channel activity (PubMed:10219239, PubMed:9230439)
Specific Function
delayed rectifier potassium channel activity
Gene Name
KCNH2
Uniprot ID
Q12809
Uniprot Name
Voltage-gated inwardly rectifying potassium channel KCNH2
Molecular Weight
126653.52 Da
References
  1. Wu PE, Juurlink DN: Clinical Review: Loperamide Toxicity. Ann Emerg Med. 2017 Aug;70(2):245-252. doi: 10.1016/j.annemergmed.2017.04.008. Epub 2017 May 13. [Article]
Kind
Protein group
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Calmodulin acts as part of a calcium signal transduction pathway by mediating the control of a large number of enzymes, ion channels, aquaporins and other proteins through calcium-binding (PubMed:16760425, PubMed:23893133, PubMed:26969752, PubMed:27165696, PubMed:28890335, PubMed:31454269, PubMed:35568036). Calcium-binding is required for the activation of calmodulin (PubMed:16760425, PubMed:23893133, PubMed:26969752, PubMed:27165696, PubMed:28890335, PubMed:31454269, PubMed:35568036). Among the enzymes to be stimulated by the calmodulin-calcium complex are a number of protein kinases, such as myosin light-chain kinases and calmodulin-dependent protein kinase type II (CaMK2), and phosphatases (PubMed:16760425, PubMed:23893133, PubMed:26969752, PubMed:27165696, PubMed:28890335, PubMed:31454269, PubMed:35568036). Together with CCP110 and centrin, is involved in a genetic pathway that regulates the centrosome cycle and progression through cytokinesis (PubMed:16760425). Is a regulator of voltage-dependent L-type calcium channels (PubMed:31454269). Mediates calcium-dependent inactivation of CACNA1C (PubMed:26969752). Positively regulates calcium-activated potassium channel activity of KCNN2 (PubMed:27165696). Forms a potassium channel complex with KCNQ1 and regulates electrophysiological activity of the channel via calcium-binding (PubMed:25441029). Acts as a sensor to modulate the endoplasmic reticulum contacts with other organelles mediated by VMP1:ATP2A2 (PubMed:28890335)
Specific Function
adenylate cyclase activator activity

Components:
References
  1. Daly JW, Harper J: Loperamide: novel effects on capacitative calcium influx. Cell Mol Life Sci. 2000 Jan 20;57(1):149-57. [Article]
  2. Suzuki T, Sakai H, Ikari A, Takeguchi N: Inhibition of thromboxane A(2)-induced Cl(-) secretion by antidiarrhea drug loperamide in isolated rat colon. J Pharmacol Exp Ther. 2000 Oct;295(1):233-8. [Article]
  3. Mellstrand T: Loperamide--an opiate receptor agonist with gastrointestinal motility effects. Scand J Gastroenterol Suppl. 1987;130:65-6. [Article]
  4. Stoll R, Ruppin H, Domschke W: Calmodulin-mediated effects of loperamide on chloride transport by brush border membrane vesicles from human ileum. Gastroenterology. 1988 Jul;95(1):69-76. [Article]
  5. Diener M, Knobloch SF, Rummel W: Action of loperamide on neuronally mediated and Ca2+- or cAMP-mediated secretion in rat colon. Eur J Pharmacol. 1988 Aug 2;152(3):217-25. [Article]
  6. Regnard C, Twycross R, Mihalyo M, Wilcock A: Loperamide. J Pain Symptom Manage. 2011 Aug;42(2):319-23. doi: 10.1016/j.jpainsymman.2011.06.001. Epub 2011 Jun 23. [Article]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
A cytochrome P450 monooxygenase involved in the metabolism of sterols, steroid hormones, retinoids and fatty acids (PubMed:10681376, PubMed:11093772, PubMed:11555828, PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:19965576, PubMed:20702771, PubMed:21490593, PubMed:21576599). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:21490593, PubMed:21576599, PubMed:2732228). Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2, as well as D-ring hydroxylated E1 and E2 at the C-16 position (PubMed:11555828, PubMed:12865317, PubMed:14559847). Plays a role in the metabolism of androgens, particularly in oxidative deactivation of testosterone (PubMed:15373842, PubMed:15764715, PubMed:22773874, PubMed:2732228). Metabolizes testosterone to less biologically active 2beta- and 6beta-hydroxytestosterones (PubMed:15373842, PubMed:15764715, PubMed:2732228). Contributes to the formation of hydroxycholesterols (oxysterols), particularly A-ring hydroxylated cholesterol at the C-4beta position, and side chain hydroxylated cholesterol at the C-25 position, likely contributing to cholesterol degradation and bile acid biosynthesis (PubMed:21576599). Catalyzes bisallylic hydroxylation of polyunsaturated fatty acids (PUFA) (PubMed:9435160). Catalyzes the epoxidation of double bonds of PUFA with a preference for the last double bond (PubMed:19965576). Metabolizes endocannabinoid arachidonoylethanolamide (anandamide) to 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:20702771). Plays a role in the metabolism of retinoids. Displays high catalytic activity for oxidation of all-trans-retinol to all-trans-retinal, a rate-limiting step for the biosynthesis of all-trans-retinoic acid (atRA) (PubMed:10681376). Further metabolizes atRA toward 4-hydroxyretinoate and may play a role in hepatic atRA clearance (PubMed:11093772). Responsible for oxidative metabolism of xenobiotics. Acts as a 2-exo-monooxygenase for plant lipid 1,8-cineole (eucalyptol) (PubMed:11159812). Metabolizes the majority of the administered drugs. Catalyzes sulfoxidation of the anthelmintics albendazole and fenbendazole (PubMed:10759686). Hydroxylates antimalarial drug quinine (PubMed:8968357). Acts as a 1,4-cineole 2-exo-monooxygenase (PubMed:11695850). Also involved in vitamin D catabolism and calcium homeostasis. Catalyzes the inactivation of the active hormone calcitriol (1-alpha,25-dihydroxyvitamin D(3)) (PubMed:29461981)
Specific Function
1,8-cineole 2-exo-monooxygenase activity
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Baker DE: Loperamide: a pharmacological review. Rev Gastroenterol Disord. 2007;7 Suppl 3:S11-8. [Article]
  2. Kim KA, Chung J, Jung DH, Park JY: Identification of cytochrome P450 isoforms involved in the metabolism of loperamide in human liver microsomes. Eur J Clin Pharmacol. 2004 Oct;60(8):575-81. Epub 2004 Sep 8. [Article]
  3. Marechal JD, Yu J, Brown S, Kapelioukh I, Rankin EM, Wolf CR, Roberts GC, Paine MJ, Sutcliffe MJ: In silico and in vitro screening for inhibition of cytochrome P450 CYP3A4 by comedications commonly used by patients with cancer. Drug Metab Dispos. 2006 Apr;34(4):534-8. doi: 10.1124/dmd.105.007625. Epub 2006 Jan 13. [Article]
  4. FDA Discontinued Drug Products: IMODIUM (loperamide) Oral Tablets [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids, steroid hormones and vitamins (PubMed:11093772, PubMed:14559847, PubMed:15766564, PubMed:19965576, PubMed:7574697). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:11093772, PubMed:14559847, PubMed:15766564, PubMed:19965576, PubMed:7574697). Primarily catalyzes the epoxidation of double bonds of polyunsaturated fatty acids (PUFA) with a preference for the last double bond (PubMed:15766564, PubMed:19965576, PubMed:7574697). Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes all trans-retinoic acid toward its 4-hydroxylated form (PubMed:11093772). Displays 16-alpha hydroxylase activity toward estrogen steroid hormones, 17beta-estradiol (E2) and estrone (E1) (PubMed:14559847). Plays a role in the oxidative metabolism of xenobiotics. It is the principal enzyme responsible for the metabolism of the anti-cancer drug paclitaxel (taxol) (PubMed:26427316)
Specific Function
arachidonic acid epoxygenase activity
Gene Name
CYP2C8
Uniprot ID
P10632
Uniprot Name
Cytochrome P450 2C8
Molecular Weight
55824.275 Da
References
  1. Kim KA, Chung J, Jung DH, Park JY: Identification of cytochrome P450 isoforms involved in the metabolism of loperamide in human liver microsomes. Eur J Clin Pharmacol. 2004 Oct;60(8):575-81. Epub 2004 Sep 8. [Article]
  2. FDA Discontinued Drug Products: IMODIUM (loperamide) Oral Tablets [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
A cytochrome P450 monooxygenase involved in the metabolism of endocannabinoids and steroids (PubMed:12865317, PubMed:21289075). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase). Catalyzes the epoxidation of double bonds of arachidonoylethanolamide (anandamide) to 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:21289075). Hydroxylates steroid hormones, including testosterone at C-16 and estrogens at C-2 (PubMed:12865317, PubMed:21289075). Plays a role in the oxidative metabolism of xenobiotics, including plant lipids and drugs (PubMed:11695850, PubMed:22909231). Acts as a 1,4-cineole 2-exo-monooxygenase (PubMed:11695850)
Specific Function
anandamide 11,12 epoxidase activity
Gene Name
CYP2B6
Uniprot ID
P20813
Uniprot Name
Cytochrome P450 2B6
Molecular Weight
56277.81 Da
References
  1. Kim KA, Chung J, Jung DH, Park JY: Identification of cytochrome P450 isoforms involved in the metabolism of loperamide in human liver microsomes. Eur J Clin Pharmacol. 2004 Oct;60(8):575-81. Epub 2004 Sep 8. [Article]
  2. FDA Discontinued Drug Products: IMODIUM (loperamide) Oral Tablets [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
A cytochrome P450 monooxygenase involved in the metabolism of fatty acids, steroids and retinoids (PubMed:18698000, PubMed:19965576, PubMed:20972997, PubMed:21289075, PubMed:21576599). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:18698000, PubMed:19965576, PubMed:20972997, PubMed:21289075, PubMed:21576599). Catalyzes the epoxidation of double bonds of polyunsaturated fatty acids (PUFA) (PubMed:19965576, PubMed:20972997). Metabolizes endocannabinoid arachidonoylethanolamide (anandamide) to 20-hydroxyeicosatetraenoic acid ethanolamide (20-HETE-EA) and 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:18698000, PubMed:21289075). Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes cholesterol toward 25-hydroxycholesterol, a physiological regulator of cellular cholesterol homeostasis (PubMed:21576599). Catalyzes the oxidative transformations of all-trans retinol to all-trans retinal, a precursor for the active form all-trans-retinoic acid (PubMed:10681376). Also involved in the oxidative metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic antidepressants
Specific Function
anandamide 11,12 epoxidase activity
Gene Name
CYP2D6
Uniprot ID
P10635
Uniprot Name
Cytochrome P450 2D6
Molecular Weight
55768.94 Da
References
  1. Kim KA, Chung J, Jung DH, Park JY: Identification of cytochrome P450 isoforms involved in the metabolism of loperamide in human liver microsomes. Eur J Clin Pharmacol. 2004 Oct;60(8):575-81. Epub 2004 Sep 8. [Article]
  2. FDA Discontinued Drug Products: IMODIUM (loperamide) Oral Tablets [Link]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Curator comments
Loperamide is a substrate for P-glycoprotein at higher doses. If P-glycoprotein becomes inhibited, loperamide can cross the blood-brain barrier and act on the central nervous system, producing central opioid effects and toxicity (Sahi et al., 2022).
General Function
Translocates drugs and phospholipids across the membrane (PubMed:2897240, PubMed:35970996, PubMed:8898203, PubMed:9038218). Catalyzes the flop of phospholipids from the cytoplasmic to the exoplasmic leaflet of the apical membrane. Participates mainly to the flop of phosphatidylcholine, phosphatidylethanolamine, beta-D-glucosylceramides and sphingomyelins (PubMed:8898203). Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells (PubMed:2897240, PubMed:35970996, PubMed:9038218)
Specific Function
ABC-type xenobiotic transporter activity
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
ATP-dependent translocase ABCB1
Molecular Weight
141477.255 Da
References
  1. Wandel C, Kim R, Wood M, Wood A: Interaction of morphine, fentanyl, sufentanil, alfentanil, and loperamide with the efflux drug transporter P-glycoprotein. Anesthesiology. 2002 Apr;96(4):913-20. [Article]
  2. Adachi Y, Suzuki H, Sugiyama Y: Comparative studies on in vitro methods for evaluating in vivo function of MDR1 P-glycoprotein. Pharm Res. 2001 Dec;18(12):1660-8. [Article]
  3. Schinkel AH, Wagenaar E, Mol CA, van Deemter L: P-glycoprotein in the blood-brain barrier of mice influences the brain penetration and pharmacological activity of many drugs. J Clin Invest. 1996 Jun 1;97(11):2517-24. [Article]
  4. Sahi N, Nguyen R, Santos C: Loperamide . [Article]
  5. FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers [Link]
  6. FDA Discontinued Drug Products: IMODIUM (loperamide) Oral Tablets [Link]

Drug created at June 13, 2005 13:24 / Updated at November 03, 2024 19:35