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 various over-the-counter products 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 ¹ that is structurally similar to opiate receptor agonists such as diphenoxylate and haloperidol.² Due to pharmacological properties, 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 for experiencing a range of adverse effects, often life-threatening, if taking for non-therapeutic reasons or at doses higher than the recommended dose.⁸

Type

Small Molecule

Groups

Approved

Structure

Similar Structures

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

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-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

Target	Actions	Organism
AMu-type opioid receptor	agonist	Humans
UDelta-type opioid receptor	agonist	Humans
UKappa-type opioid receptor	agonist	Humans
UCalmodulin	inhibitor	Humans
UPro-opiomelanocortin	modulator	Humans
NVoltage-dependent P/Q-type calcium channel subunit alpha-1A	blocker	Humans
NPotassium voltage-gated channel subfamily H member 2	blocker	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

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Loperamide

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

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.

Drug	Interaction
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Abametapir	The serum concentration of Loperamide can be increased when it is combined with Abametapir.
Abatacept	The metabolism of Loperamide can be increased when combined with Abatacept.
Abemaciclib	The serum concentration of Abemaciclib can be increased when it is combined with Loperamide.
Abiraterone	The metabolism of Loperamide can be decreased when combined with Abiraterone.
Abrocitinib	The excretion of Loperamide can be decreased when combined with Abrocitinib.
Acarbose	The risk or severity of hypoglycemia can be increased when Loperamide is combined with Acarbose.
Acebutolol	Loperamide may increase the arrhythmogenic activities of Acebutolol.
Aceclofenac	The risk or severity of hyperkalemia can be increased when Loperamide is combined with Aceclofenac.
Acemetacin	The risk or severity of hyperkalemia can be increased when Loperamide is combined with Acemetacin.
Acetohexamide	The risk or severity of hypoglycemia can be increased when Loperamide is combined with Acetohexamide.

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Food Interactions

Not Available

Products

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Product Ingredients

Ingredient	UNII	CAS	InChI Key
Loperamide hydrochloride	77TI35393C	34552-83-5	PGYPOBZJRVSMDS-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

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Imodium	Capsule	2 mg/1	Oral	McNeil Consumer Healthcare	2008-02-26	Not applicable

Generic Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
Loperamide Hydrochloride	Capsule	2 mg/1	Oral	PD-Rx Pharmaceuticals, Inc.	1991-09-18	2019-09-20
Loperamide hydrochloride	Capsule	2 mg/1	Oral	Northwind Pharmaceuticals	2014-10-22	Not applicable
Loperamide Hydrochloride	Capsule	2 mg/1	Oral	Cardinal Health	1997-03-10	2030-01-31
Loperamide Hydrochloride	Capsule	2 mg/1	Oral	bryant ranch prepack	1993-05-01	Not applicable
Loperamide Hydrochloride	Capsule	2 mg/1	Oral	Remedy Repack	2012-09-12	2017-01-23
Loperamide Hydrochloride	Capsule	2 mg/1	Oral	Nucare Pharmaceuticals, Inc.	1993-05-01	Not applicable
Loperamide Hydrochloride	Capsule	2 mg/1	Oral	bryant ranch prepack	1993-05-01	Not applicable
Loperamide Hydrochloride	Capsule	2 mg/1	Oral	Physicians Total Care, Inc.	1996-06-20	Not applicable
Loperamide Hydrochloride	Capsule	2 mg/1	Oral	A-S Medication Solutions	1993-05-01	2013-10-28
Loperamide Hydrochloride	Capsule	2 mg/1	Oral	Ncs Health Care Of Ky, Inc Dba Vangard Labs	1991-09-18	Not applicable

Over the Counter Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
7 Select Anti Diarrheal	Solution	1 mg/7.5mL	Oral	7-Eleven	2018-08-07	2021-04-30
7 Select Anti Diarrheal	Tablet, film coated	2 mg/1	Oral	7-Eleven	2014-08-05	2021-02-28
A D	Tablet, film coated	2 mg/1	Oral	Western Family Foods	2003-04-10	2017-08-12
A D	Tablet, film coated	2 mg/1	Oral	Western Family Foods	2003-02-25	2017-08-29
Alti-loperamide - 2mg Caplet	Tablet	2 mg	Oral	Altimed Pharma Inc.	1995-12-31	1997-08-14
Anti Diarrheal	Tablet, film coated	2 mg/1	Oral	Shopko Stores Operating Co., LLC	2003-03-07	Not applicable
Anti Diarrheal	Tablet, film coated	2 mg/1	Oral	Walgreen Company	2021-09-11	Not applicable
Anti Diarrheal	Solution	1 mg/5mL	Oral	Rite Aid	1992-07-13	2015-06-12
Anti Diarrheal	Tablet	2 mg/1	Oral	CHAIN DRUG MARKETING ASSOCIATION INC	2005-05-03	Not applicable
Anti Diarrheal	Tablet, film coated	2 mg/1	Oral	Major Pharmaceuticals	2003-02-24	Not applicable

Mixture Products

Name	Ingredients	Dosage	Route	Labeller	Marketing Start	Marketing End
Anti Diarrheal and Anti Gas	Loperamide hydrochloride (2 mg/1) + Dimethicone (125 mg/1)	Tablet	Oral	Walgreen Company	2018-10-10	Not applicable
Anti Diarrheal and Anti Gas	Loperamide hydrochloride (2 mg/1) + Dimethicone (125 mg/1)	Tablet	Oral	CVS PHARMACY	2019-08-06	Not applicable
Anti Diarrheal Anti Gas	Loperamide hydrochloride (2 mg/1) + Dimethicone (125 mg/1)	Tablet	Oral	H E B	2018-11-15	Not applicable
Anti Diarrheal Anti Gas	Loperamide hydrochloride (2 mg/1) + Dimethicone (125 mg/1)	Tablet	Oral	Amerisource Bergen	2018-12-28	Not applicable
Anti Diarrheal Anti Gas	Loperamide hydrochloride (2 mg/1) + Dimethicone (125 mg/1)	Tablet	Oral	Rite Aid Corporation	2019-01-03	Not applicable
Anti Diarrheal Anti Gas	Loperamide hydrochloride (2 mg/1) + Dimethicone (125 mg/1)	Tablet	Oral	Kroger Company	2019-04-24	Not applicable
Anti Diarrheal Plus Anti Gas	Loperamide hydrochloride (2 mg/1) + Dimethicone (125 mg/1)	Tablet	Oral	Meijer Distribution Inc	2018-10-16	Not applicable
Anti-Diarrheal/Anti-Gas Multi-Symptom Relief	Loperamide hydrochloride (2 mg/1) + Dimethicone (125 mg/1)	Tablet	Oral	Wal-Mart Stores, Inc.	2022-07-15	Not applicable
Antidiarrheal Multi Symptom Relief	Loperamide hydrochloride (2 mg/1) + Dimethicone (125 mg/1)	Tablet	Oral	Publix Super Markets Inc	2020-08-03	Not applicable
Basic Care Loperamide Hydrochloride and Simethicone	Loperamide hydrochloride (2 mg/1) + Dimethicone (125 mg/1)	Tablet	Oral	Amazon.com Services LLC	2020-06-24	Not applicable

Unapproved/Other Products

Name	Ingredients	Dosage	Route	Labeller	Marketing Start	Marketing End	Region	Image
Gadavyt Loperamide HCl	Loperamide hydrochloride (1 mg/5mL)	Liquid	Oral	Gadal Laboratories, Inc.	2013-05-01	Not applicable
Meds on the Go	Loperamide 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)	Kit	Oral	Doc In The Box Llc	2019-01-01	Not applicable

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

Sahi N, Nguyen R, Santos C: Loperamide . [Article]
Baker DE: Loperamide: a pharmacological review. Rev Gastroenterol Disord. 2007;7 Suppl 3:S11-8. [Article]
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]
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]
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]
Thermo Fisher Scientific: Loperamide hydrochloride MSDS [Link]
DailyMed Label: ANTI-DIARRHEAL (loperamide hcl) Oral Tablet [Link]
FDA Discontinued Drug Products: IMODIUM (loperamide) Oral Tablets [Link]

External Links

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

Phase	Status	Purpose	Conditions	Count
4	Completed	Treatment	Diarrhea	3
4	Completed	Treatment	Opioid Withdrawal (Disorder)	1
4	Completed	Treatment	Traveler's Diarrhea	1
4	Suspended	Treatment	Antibiotic Associated Diarrhoea / Clostridium Difficile	1
4	Terminated	Treatment	Relapsing Remitting Multiple Sclerosis (RRMS)	1
4	Withdrawn	Treatment	Fecal Incontinence	1
3	Completed	Supportive Care	Colorectal Cancer / Diarrhea	1
3	Completed	Treatment	Diarrhea	1
3	Completed	Treatment	Fecal Incontinence	1
3	Completed	Treatment	Non-Small Cell Lung Carcinoma (NSCLC)	1

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

Form	Route	Strength
Suspension	Oral	20 mg
Solution	Oral	1 mg/5mL
Tablet, coated	Oral	2 mg/1
Solution / drops	Oral
Capsule	Oral	2.00 MG
Suspension	Oral	40 mg
Syrup	Oral	1 mg/5ml
Syrup	Oral
Kit	Oral
Solution	Oral	.2 mg / mL
Liquid	Oral	1 mg/5mL
Tablet	Oral
Capsule	Oral	2 mg/1
Capsule, coated	Oral	2 mg
Tablet, chewable	Oral
Tablet, film coated	Oral
Capsule	Oral
Solution	Oral	1 mg/7.5mL
Tablet, chewable	Oral	2 mg/1
Tablet, orally disintegrating	Oral
Solution	Oral	2 mg / 15 mL
Capsule	Oral	2 mg / cap
Tablet	Oral	2 mg / tab
Solution	Oral	0.2 mg
Liquid	Oral	.2 mg / mL
Tablet, orally disintegrating	Oral	2 mg
Solution	Oral
Capsule	Oral
Tablet	Oral	2 MG
Solution	Oral	0.2 MG/ML
Solution	Oral	2 mg
Tablet	Oral	0.002 g
Solution	Oral	2 MG/ML
Tablet, effervescent	Oral	2 MG
Capsule, liquid filled	Oral	2 mg/1
Liquid	Oral	1 mg/7.5mL
Solution	Oral	2 mg/10mL
Solution	Oral	2 mg/15mL
Tablet	Oral	2 mg/1
Tablet	Oral
Syrup	Oral	1.05 mg/5ml
Tablet, effervescent	Oral
Tablet		2 MG
Tablet, coated	Oral	2 mg
Tablet, film coated	Oral	2 mg/1
Solution	Oral	0.2 mg / mL
Suspension	Oral	1 mg/7.5mL
Syrup	Oral	20 mg
Capsule	Oral	2 mg
Injection, powder, for solution		200 MG
Injection, powder, for solution		400 MG
Tablet, film coated	Oral	2 mg

Prices

Unit description	Cost	Unit
Loperamide hcl powder	26.01USD	g
Loperamide HCl 2 mg capsule	0.64USD	capsule
Imodium a-d 2 mg caplet	0.49USD	caplet
Imodium advanced caplet	0.46USD	caplet
Imodium ms relief caplet	0.46USD	caplet
Kaopectate 262 mg caplet	0.37USD	caplet
Loperamide 2 mg caplet	0.37USD	caplet
Qc anti-diarrheal adv caplet	0.3USD	caplet
Diamode 2 mg tablet	0.28USD	tablet
Kaopectate 240 mg softgel	0.25USD	softgel capsule
Anti-diarrheal 2 mg caplet	0.18USD	caplet
CVS Pharmacy anti-diarrheal 2 mg caplet	0.14USD	caplet
Kaopectate children's suspension	0.02USD	ml

DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)
CA2134611	No	2002-12-24	2014-10-28
US6814978	Yes	2004-11-09	2022-02-26
US6103260	No	2000-08-15	2017-07-17

Properties

State

Solid

Experimental Properties

Property	Value	Source
melting point (°C)	220-228	https://www.medisca.com/NDC_SPECS/MUS/0446/MSDS/0446.pdf
logP	5.13	https://www.medisca.com/NDC_SPECS/MUS/0446/MSDS/0446.pdf

Predicted Properties

Property	Value	Source
Water Solubility	0.00086 mg/mL	ALOGPS
logP	4.44	ALOGPS
logP	4.77	ChemAxon
logS	-5.7	ALOGPS
pKa (Strongest Acidic)	13.96	ChemAxon
pKa (Strongest Basic)	9.41	ChemAxon
Physiological Charge	1	ChemAxon
Hydrogen Acceptor Count	3	ChemAxon
Hydrogen Donor Count	1	ChemAxon
Polar Surface Area	43.78 Å²	ChemAxon
Rotatable Bond Count	7	ChemAxon
Refractivity	139.32 m³·mol^-1	ChemAxon
Polarizability	52.59 Å³	ChemAxon
Number of Rings	4	ChemAxon
Bioavailability	1	ChemAxon
Rule of Five	Yes	ChemAxon
Ghose Filter	No	ChemAxon
Veber's Rule	No	ChemAxon
MDDR-like Rule	Yes	ChemAxon

Predicted ADMET Features

Property	Value	Probability
Human Intestinal Absorption	+	0.9878
Blood Brain Barrier	+	0.7709
Caco-2 permeable	+	0.5875
P-glycoprotein substrate	Substrate	0.7476
P-glycoprotein inhibitor I	Inhibitor	0.8277
P-glycoprotein inhibitor II	Inhibitor	0.8387
Renal organic cation transporter	Inhibitor	0.5059
CYP450 2C9 substrate	Non-substrate	0.8057
CYP450 2D6 substrate	Non-substrate	0.5315
CYP450 3A4 substrate	Substrate	0.7918
CYP450 1A2 substrate	Non-inhibitor	0.9045
CYP450 2C9 inhibitor	Non-inhibitor	0.9154
CYP450 2D6 inhibitor	Inhibitor	0.8933
CYP450 2C19 inhibitor	Non-inhibitor	0.9026
CYP450 3A4 inhibitor	Non-inhibitor	0.8309
CYP450 inhibitory promiscuity	Low CYP Inhibitory Promiscuity	0.9207
Ames test	Non AMES toxic	0.768
Carcinogenicity	Non-carcinogens	0.8564
Biodegradation	Not ready biodegradable	0.9953
Rat acute toxicity	3.6560 LD50, mol/kg	Not applicable
hERG inhibition (predictor I)	Weak inhibitor	0.9461
hERG inhibition (predictor II)	Inhibitor	0.7639

ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted GC-MS Spectrum - GC-MS	Predicted GC-MS	Not Available
MS/MS Spectrum - Quattro_QQQ 10V, Positive	LC-MS/MS	splash10-004i-0000900000-673950710672b433271c
MS/MS Spectrum - Quattro_QQQ 25V, Positive	LC-MS/MS	splash10-014i-0090000000-4b7b347a8b8e9dca406c
MS/MS Spectrum - Quattro_QQQ 40V, Positive	LC-MS/MS	splash10-02t9-0090000000-31f15df976e23e73330a
LC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 10V, Positive	LC-MS/MS	splash10-004i-0000900000-d91d13c4e4665bd5fb5a
LC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 20V, Positive	LC-MS/MS	splash10-004i-0020900000-f1be3181a6918c985ffd
LC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 30V, Positive	LC-MS/MS	splash10-014i-0090000000-e5e41346303f41f65688
LC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 40V, Positive	LC-MS/MS	splash10-014i-0090000000-acd8b87c1338e5d0fe25
LC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 50V, Positive	LC-MS/MS	splash10-014i-0090000000-81b85f788d14641430fd
LC-MS/MS Spectrum - LC-ESI-IT (LC/MSD Trap XCT, Agilent Technologies) , Positive	LC-MS/MS	splash10-014i-0090000000-3ce1a89454d777268799
LC-MS/MS Spectrum - LC-ESI-IT (LC/MSD Trap XCT, Agilent Technologies) , Positive	LC-MS/MS	splash10-03di-0090000000-f101d63ad0bf8e5d2178
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
LC-MS/MS Spectrum - LC-ESI-QQ , positive	LC-MS/MS	splash10-004i-0000900000-d91d13c4e4665bd5fb5a
LC-MS/MS Spectrum - LC-ESI-QQ , positive	LC-MS/MS	splash10-004i-0020900000-f1be3181a6918c985ffd
LC-MS/MS Spectrum - LC-ESI-QQ , positive	LC-MS/MS	splash10-014i-0090000000-e5e41346303f41f65688
LC-MS/MS Spectrum - LC-ESI-QQ , positive	LC-MS/MS	splash10-014i-0090000000-acd8b87c1338e5d0fe25
LC-MS/MS Spectrum - LC-ESI-QQ , positive	LC-MS/MS	splash10-014i-0090000000-81b85f788d14641430fd
LC-MS/MS Spectrum - LC-ESI-IT , positive	LC-MS/MS	splash10-014i-0090000000-1a1a49f09397ad090e82
MS/MS Spectrum - , positive	LC-MS/MS	splash10-016r-0090600000-794ea6214c0cd97c73fa
LC-MS/MS Spectrum - LC-ESI-QFT , positive	LC-MS/MS	splash10-016r-0090300000-e11942e343a28799a5ab
1H NMR Spectrum	1D NMR	Not Applicable
[1H,13C] 2D NMR Spectrum	2D NMR	Not Applicable

Targets

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Property	Measurement	pH	Temperature (°C)	References
EC 50 (nM)	58	N/A	N/A	A29123
Ki (nM)	0.53	N/A	N/A	A29122

Details1. Mu-type opioid receptor

Kind: Protein
Organism: Humans
Pharmacological action: Yes
Actions: Agonist

General Function: Voltage-gated calcium channel activity
Specific Function: Receptor for endogenous opioids such as beta-endorphin and endomorphin. Receptor for natural and synthetic opioids including morphine, heroin, DAMGO, fentanyl, etorphine, buprenorphin and methadone...
Gene Name: OPRM1
Uniprot ID: P35372
Uniprot Name: Mu-type opioid receptor
Molecular Weight: 44778.855 Da

References

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]
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]
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]
Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
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]
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]

Details2. Delta-type opioid receptor

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Agonist

General Function: Opioid receptor activity
Specific Function: G-protein coupled receptor that functions as receptor for endogenous enkephalins and for a subset of other opioids. Ligand binding causes a conformation change that triggers signaling via guanine n...
Gene Name: OPRD1
Uniprot ID: P41143
Uniprot Name: Delta-type opioid receptor
Molecular Weight: 40368.235 Da

References

Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
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]
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]

Details3. Kappa-type opioid receptor

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Agonist

General Function: Opioid receptor activity
Specific Function: G-protein coupled opioid receptor that functions as receptor for endogenous alpha-neoendorphins and dynorphins, but has low affinity for beta-endorphins. Also functions as receptor for various synt...
Gene Name: OPRK1
Uniprot ID: P41145
Uniprot Name: Kappa-type opioid receptor
Molecular Weight: 42644.665 Da

References

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]

Details4. Calmodulin

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Inhibitor

General Function: Titin binding
Specific Function: Calmodulin mediates the control of a large number of enzymes, ion channels, aquaporins and other proteins by Ca(2+). Among the enzymes to be stimulated by the calmodulin-Ca(2+) complex are a number...
Gene Name: CALM1
Uniprot ID: P0DP23
Uniprot Name: Calmodulin
Molecular Weight: 16837.47 Da

References

Daly JW, Harper J: Loperamide: novel effects on capacitative calcium influx. Cell Mol Life Sci. 2000 Jan 20;57(1):149-57. [Article]
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]
Mellstrand T: Loperamide--an opiate receptor agonist with gastrointestinal motility effects. Scand J Gastroenterol Suppl. 1987;130:65-6. [Article]
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]
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]
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]

Details5. Pro-opiomelanocortin

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Modulator

General Function: Type 4 melanocortin receptor binding
Specific Function: ACTH stimulates the adrenal glands to release cortisol.MSH (melanocyte-stimulating hormone) increases the pigmentation of skin by increasing melanin production in melanocytes.Beta-endorphin and Met...
Gene Name: POMC
Uniprot ID: P01189
Uniprot Name: Pro-opiomelanocortin
Molecular Weight: 29423.72 Da

References

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]
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]
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]
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]
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]

Details6. Voltage-dependent P/Q-type calcium channel subunit alpha-1A

Kind: Protein
Organism: Humans
Pharmacological action: No
Actions: Blocker

General Function: Voltage-gated calcium channel activity
Specific 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, hor...
Gene Name: CACNA1A
Uniprot ID: O00555
Uniprot Name: Voltage-dependent P/Q-type calcium channel subunit alpha-1A
Molecular Weight: 282362.39 Da

References

Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [Article]
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]
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]

Details7. Potassium voltage-gated channel subfamily H member 2

Kind: Protein
Organism: Humans
Pharmacological action: No
Actions: Blocker

General Function: Voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization
Specific Function: Pore-forming (alpha) subunit of voltage-gated inwardly rectifying potassium channel. Channel properties are modulated by cAMP and subunit assembly. Mediates the rapidly activating component of the ...
Gene Name: KCNH2
Uniprot ID: Q12809
Uniprot Name: Potassium voltage-gated channel subfamily H member 2
Molecular Weight: 126653.52 Da

References

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]

Enzymes

Details1. Cytochrome P450 3A4

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Substrate
Inhibitor

General Function: Vitamin d3 25-hydroxylase activity
Specific Function: Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name: CYP3A4
Uniprot ID: P08684
Uniprot Name: Cytochrome P450 3A4
Molecular Weight: 57342.67 Da

References

Baker DE: Loperamide: a pharmacological review. Rev Gastroenterol Disord. 2007;7 Suppl 3:S11-8. [Article]
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]
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]
FDA Discontinued Drug Products: IMODIUM (loperamide) Oral Tablets [Link]

Details2. Cytochrome P450 2C8

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Substrate

General Function: Steroid hydroxylase activity
Specific Function: Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name: CYP2C8
Uniprot ID: P10632
Uniprot Name: Cytochrome P450 2C8
Molecular Weight: 55824.275 Da

References

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]
FDA Discontinued Drug Products: IMODIUM (loperamide) Oral Tablets [Link]

Details3. Cytochrome P450 2B6

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Substrate

General Function: Steroid hydroxylase activity
Specific Function: Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name: CYP2B6
Uniprot ID: P20813
Uniprot Name: Cytochrome P450 2B6
Molecular Weight: 56277.81 Da

References

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]
FDA Discontinued Drug Products: IMODIUM (loperamide) Oral Tablets [Link]

Details4. Cytochrome P450 2D6

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Substrate

General Function: Steroid hydroxylase activity
Specific Function: Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic...
Gene Name: CYP2D6
Uniprot ID: P10635
Uniprot Name: Cytochrome P450 2D6
Molecular Weight: 55768.94 Da

References

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]
FDA Discontinued Drug Products: IMODIUM (loperamide) Oral Tablets [Link]

Transporters

Property	Measurement	pH	Temperature (°C)	References
IC 50 (nM)	2500	N/A	N/A	A16161

Details1. P-glycoprotein 1

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: Xenobiotic-transporting atpase activity
Specific Function: Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name: ABCB1
Uniprot ID: P08183
Uniprot Name: Multidrug resistance protein 1
Molecular Weight: 141477.255 Da

References

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]
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]
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]
Sahi N, Nguyen R, Santos C: Loperamide . [Article]
FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers [Link]
FDA Discontinued Drug Products: IMODIUM (loperamide) Oral Tablets [Link]

Drug created at June 13, 2005 13:24 / Updated at October 04, 2022 23:16

Loperamide

Identification

Structure for Loperamide (DB00836)

Pharmacology

Interactions

Products

Categories

Chemical Identifiers

References

Clinical Trials

Pharmacoeconomics

Properties

Spectra

Targets

References

References

References

References

References

References

References

Enzymes

References

References

References

References

Transporters

References