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Loperamide

PubChem CID
3955
Structure
Loperamide_small.png
Loperamide_3D_Structure.png
Molecular Formula
Synonyms
  • loperamide
  • 53179-11-6
  • Ioperamide
  • Loperamida
  • Loperamidum
Molecular Weight
477.0 g/mol
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Dates
  • Create:
    2005-03-25
  • Modify:
    2024-12-27
Description
Loperamide is a synthetic piperidine derivative, effective against diarrhoea resulting from gastroenteritis or inflammatory bowel disease. It has a role as a mu-opioid receptor agonist, an antidiarrhoeal drug and an anticoronaviral agent. It is a member of piperidines, a monocarboxylic acid amide, a member of monochlorobenzenes and a tertiary alcohol. It is a conjugate base of a loperamide(1+).
Loperamide is an anti-diarrheal agent that is available as various over-the-counter products for treating diarrhea. The drug was first synthesized in 1969 and used medically in 1976. It is a highly lipophilic synthetic phenylpiperidine opioid that is structurally similar to opiate receptor agonists such as [diphenoxylate] and [haloperidol]. Due to pharmacological properties, loperamide has been misused and abused to self-manage opioid withdrawal symptoms and to induce euphoria. 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.
Loperamide is an Opioid Agonist. The mechanism of action of loperamide is as an Opioid Agonist.

1 Structures

1.1 2D Structure

Chemical Structure Depiction
Loperamide.png

1.2 3D Conformer

1.3 Crystal Structures

COD records with this CID as component

2 Names and Identifiers

2.1 Computed Descriptors

2.1.1 IUPAC Name

4-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-N,N-dimethyl-2,2-diphenylbutanamide
Computed by Lexichem TK 2.7.0 (PubChem release 2021.10.14)

2.1.2 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
Computed by InChI 1.0.6 (PubChem release 2021.10.14)

2.1.3 InChIKey

RDOIQAHITMMDAJ-UHFFFAOYSA-N
Computed by InChI 1.0.6 (PubChem release 2021.10.14)

2.1.4 SMILES

CN(C)C(=O)C(CCN1CCC(CC1)(C2=CC=C(C=C2)Cl)O)(C3=CC=CC=C3)C4=CC=CC=C4
Computed by OEChem 2.3.0 (PubChem release 2021.10.14)

2.2 Molecular Formula

C29H33ClN2O2
Computed by PubChem 2.2 (PubChem release 2021.10.14)

2.3 Other Identifiers

2.3.1 CAS

53179-11-6

2.3.3 European Community (EC) Number

2.3.4 UNII

2.3.5 ChEBI ID

2.3.6 ChEMBL ID

2.3.7 DrugBank ID

2.3.8 DSSTox Substance ID

2.3.9 HMDB ID

2.3.10 KEGG ID

2.3.11 Metabolomics Workbench ID

2.3.12 NCI Thesaurus Code

2.3.13 Nikkaji Number

2.3.14 PharmGKB ID

2.3.15 Pharos Ligand ID

2.3.16 RXCUI

2.3.17 Wikidata

2.3.18 Wikipedia

2.4 Synonyms

2.4.1 MeSH Entry Terms

  • Hydrochloride, Loperamide
  • Imodium
  • Loperamide
  • Loperamide Hydrochloride
  • Loperamide Monohydrochloride
  • Monohydrochloride, Loperamide
  • R 18553
  • R-18553
  • R18553

2.4.2 Depositor-Supplied Synonyms

3 Chemical and Physical Properties

3.1 Computed Properties

Property Name
Molecular Weight
Property Value
477.0 g/mol
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
XLogP3-AA
Property Value
5
Reference
Computed by XLogP3 3.0 (PubChem release 2021.10.14)
Property Name
Hydrogen Bond Donor Count
Property Value
1
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Hydrogen Bond Acceptor Count
Property Value
3
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Rotatable Bond Count
Property Value
7
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Exact Mass
Property Value
476.2230560 Da
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
Monoisotopic Mass
Property Value
476.2230560 Da
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
Topological Polar Surface Area
Property Value
43.8Ų
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Heavy Atom Count
Property Value
34
Reference
Computed by PubChem
Property Name
Formal Charge
Property Value
0
Reference
Computed by PubChem
Property Name
Complexity
Property Value
623
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Isotope Atom Count
Property Value
0
Reference
Computed by PubChem
Property Name
Defined Atom Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Undefined Atom Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Defined Bond Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Undefined Bond Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Covalently-Bonded Unit Count
Property Value
1
Reference
Computed by PubChem
Property Name
Compound Is Canonicalized
Property Value
Yes
Reference
Computed by PubChem (release 2021.10.14)

3.2 Experimental Properties

3.2.1 Physical Description

Solid

3.2.2 Melting Point

3.2.3 LogP

3.2.4 Ionization Efficiency

Ionization mode
Positive
logIE
5.26360044
pH
2.7
Instrument
Thermo LTQ
Ion source
Electrospray ionization
Additive
formic acid (5.3nM)
Organic modifier
MeCN (80%)
Reference

3.2.5 Collision Cross Section

222.7 Ų [M+H]+ [CCS Type: TW; Method: Major Mix IMS/Tof Calibration Kit (Waters)]

196.27 Ų [M+H-H2O]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

218.84 Ų [M+H]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

Ross et al. JASMS 2022; 33; 1061-1072. DOI:10.1021/jasms.2c00111

3.2.6 Other Experimental Properties

Crystals from isopropanol. MP: 222-223 °C. UV Max (0.1N HCl.2-propanol, 10.90 v/v): 253, 259, 265, 273 nm (epsilon 532, 648, 581, 233). Freely soluble in chloroform; slightly soluble in dilute acids; very slightly soluble in isopropyl alcohol. Solubility (g/100 mL): water (pH 7.1) 0.14; citrate-phosphate (pH 6.1) 0.008; methanol 28.6; ethanol 5.37; 2-propanol 1.11; dichloromethane 35.1; acetone 0.20; ethyl acetate 0.035; diethyl ether <0.001; hexane <0.001; toluene 0.001; N,N-dimethylformamide 10.2; tetrahydrofuran 0.32; 4-methyl-2-pentanone 0.02; propylene glycol 5.64; polyethylene glycol 400 1.40; dimethylsulfoxide 20.5; 2-butanone 0.18. pKa 8.66. Practically insoluble at physiological pH (0.002%). Stable, can be stored for several years under normal conditions; not hygroscopic; not affected by light /Loperamide hydrochloride/
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 1035

3.3 Chemical Classes

Pharmaceutical

3.3.1 Drugs

Pharmaceuticals -> Listed in ZINC15
S55 | ZINC15PHARMA | Pharmaceuticals from ZINC15 | DOI:10.5281/zenodo.3247749
Pharmaceuticals
S10 | SWISSPHARMA | Pharmaceutical List with Consumption Data | DOI:10.5281/zenodo.2623484
3.3.1.1 Human Drugs
Breast Feeding; Lactation; Milk, Human; Antidiarrheals; Gastrointestinal Agents
Pharmaceuticals
S72 | NTUPHTW | Pharmaceutically Active Substances from National Taiwan University | DOI:10.5281/zenodo.3955664
Medicines for other common symptoms in palliative care

4 Spectral Information

4.1 1D NMR Spectra

4.1.1 1H NMR Spectra

Spectra ID
Instrument Type
Bruker
Frequency
600 MHz
Solvent
CDCl3
pH
Not Applic
Shifts [ppm]:Intensity
7.38:100.00, 7.31:10.49, 2.82:5.57, 7.33:25.78, 7.43:14.93, 7.43:39.91, 2.82:5.33, 2.94:85.34, 7.31:16.94, 7.27:15.95, 7.33:14.26, 7.38:81.17, 2.79:13.16, 7.27:46.54, 7.27:33.03, 7.42:61.35, 2.72:8.02, 7.41:75.26, 7.32:42.66, 1.77:14.00, 7.26:38.36, 7.31:8.73, 2.29:93.32, 7.37:43.88, 7.33:17.23, 2.80:14.98, 7.40:75.89, 2.77:18.39, 2.74:4.48, 1.79:14.42, 2.73:10.69, 2.69:17.76, 3.27:11.16, 7.42:11.48
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4.2 2D NMR Spectra

4.2.1 1H-13C NMR Spectra

2D NMR Spectra Type
1H-13C HSQC
Spectra ID
Instrument Type
Bruker
Frequency
600 MHz
Solvent
CDCl3
pH
Not Applic
Shifts [ppm] (F2:F1):Intensity
7.40:127.81:0.31, 2.78:39.04:0.11, 7.27:128.66:0.41, 7.39:129.12:0.31, 7.41:129.12:0.61, 3.28:49.13:0.29, 7.39:127.83:1.00, 7.32:127.79:0.46, 1.79:35.31:0.11, 2.29:39.23:0.60, 2.80:35.31:0.14, 3.20:49.08:0.18, 2.72:55.59:0.12, 2.94:37.22:0.83, 7.43:126.13:0.43
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4.3 Mass Spectrometry

4.3.1 GC-MS

1 of 5
View All
NIST Number
247826
Library
Main library
Total Peaks
175
m/z Top Peak
238
m/z 2nd Highest
72
m/z 3rd Highest
239
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2 of 5
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NIST Number
298719
Library
Replicate library
Total Peaks
79
m/z Top Peak
238
m/z 2nd Highest
42
m/z 3rd Highest
239
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4.3.2 MS-MS

1 of 7
View All
Spectra ID
Ionization Mode
Positive
Top 5 Peaks

266.1547 100

267.1572 36.23

210.1273 22.76

238.1222 3.26

211.1301 2.72

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2 of 7
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Spectra ID
Ionization Mode
Positive
Top 5 Peaks

266.1547 100

267.157 42.06

477.2299 4.11

268.1597 2.81

210.1268 2.62

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4.3.3 LC-MS

1 of 32
View All
Authors
Nikiforos Alygizakis, Katerina Galani, Nikolaos Thomaidis, University of Athens
Instrument
Bruker maXis Impact
Instrument Type
LC-ESI-QTOF
MS Level
MS2
Ionization Mode
POSITIVE
Ionization
ESI
Collision Energy
10 eV
Fragmentation Mode
CID
Column Name
Acclaim RSLC C18 2.2um, 2.1x100mm, Thermo
Retention Time
8.297 min
Precursor m/z
477.2303
Precursor Adduct
[M+H]+
Top 5 Peaks

477.2304 999

479.2282 312

478.2332 307

266.1532 35

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License
CC BY
2 of 32
View All
Authors
Nikiforos Alygizakis, Katerina Galani, Nikolaos Thomaidis, University of Athens
Instrument
Bruker maXis Impact
Instrument Type
LC-ESI-QTOF
MS Level
MS2
Ionization Mode
POSITIVE
Ionization
ESI
Collision Energy
20 eV
Fragmentation Mode
CID
Column Name
Acclaim RSLC C18 2.2um, 2.1x100mm, Thermo
Retention Time
8.289 min
Precursor m/z
477.2303
Precursor Adduct
[M+H]+
Top 5 Peaks

266.1538 999

477.2299 843

479.2278 226

478.2331 207

267.1567 172

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License
CC BY

4.4 IR Spectra

4.4.1 ATR-IR Spectra

Instrument Name
Bio-Rad FTS
Technique
ATR-Film (MeCl2) (DuraSamplIR II)
Source of Spectrum
Forensic Spectral Research
Source of Sample
Riedel-De Haen Vetranal, Sigma-Aldrich Inc.
Catalog Number
Free base of 34014
Lot Number
Free base of 6108X
Copyright
Copyright © 2012-2024 John Wiley & Sons, Inc. All Rights Reserved.
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6 Chemical Vendors

7 Drug and Medication Information

7.1 Drug Indication

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

7.2 LiverTox Summary

Loperamide is synthetic opioid that primarily affects opiate receptors in the intestine and is used to treat diarrhea. Loperamide has not been linked to serum enzyme elevations during therapy or to clinically apparent liver injury.

7.3 Drug Classes

Breast Feeding; Lactation; Milk, Human; Antidiarrheals; Gastrointestinal Agents
Gastrointestinal Agents; Opioids

7.4 WHO Essential Medicines

Drug
Drug Classes
Medicines for other common symptoms in palliative care
Formulation
Oral - Solid - dosage form: 2 mg
Indication
Palliative care

7.5 Clinical Trials

7.5.1 ClinicalTrials.gov

7.5.2 EU Clinical Trials Register

7.6 Therapeutic Uses

Antidiarrheals
National Library of Medicine's Medical Subject Headings. Loperamide. Online file (MeSH, 2016). Available from, as of June 24, 2016: https://www.nlm.nih.gov/mesh/2016/mesh_browser/MBrowser.html
/CLINICAL TRIALS/ ClinicalTrials.gov is a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world. The Web site is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each ClinicalTrials.gov record presents summary information about a study protocol and includes the following: Disease or condition; Intervention (for example, the medical product, behavior, or procedure being studied); Title, description, and design of the study; Requirements for participation (eligibility criteria); Locations where the study is being conducted; Contact information for the study locations; and Links to relevant information on other health Web sites, such as NLM's MedlinePlus for patient health information and PubMed for citations and abstracts for scholarly articles in the field of medicine. Loperamide is included in the database.
NIH/NLM; ClinicalTrials.Gov. Available from, as of July 6, 2016: https://clinicaltrials.gov/search/intervention=Loperamide
Loperamide is used in the control and symptomatic relief of acute nonspecific diarrhea and of chronic diarrhea associated with inflammatory bowel disease. /Included in US product label/
American Society of Health-System Pharmacists 2016; Drug Information 2016. Bethesda, MD. 2016, p. 2970
The fixed combination containing loperamide and simethicone is used for the control and symptomatic relief of diarrhea when relief of flatulence, bloating, and gas pain also is indicated. /Included in US product label/
American Society of Health-System Pharmacists 2016; Drug Information 2016. Bethesda, MD. 2016, p. 2970
For more Therapeutic Uses (Complete) data for Loperamide (7 total), please visit the HSDB record page.

7.7 Drug Warnings

Loperamide is generally well tolerated; however, abdominal pain, distention or discomfort, constipation, drowsiness, dizziness, fatigue, dry mouth, nausea and vomiting, and epigastric pain may occur. Children may be more sensitive to adverse CNS effects of the drug than adults. Hypersensitivity reactions including rash have been reported. Adverse effects of loperamide are difficult to distinguish from symptoms associated with the diarrheal syndrome, but adverse GI effects are reported to be less frequent after administration of loperamide than after administration of diphenoxylate with atropine. In postmarketing experiences, paralytic ileus associated with abdominal distention has been reported rarely. Most of these cases occurred in patients with acute dysentery, following overdosage of the drug, or in children younger than 2 years of age.
American Society of Health-System Pharmacists 2016; Drug Information 2016. Bethesda, MD. 2016, p. 2970
Safety and efficacy of loperamide in children younger than 2 years of age have not been established. Loperamide should be used with particular caution in young children because of the greater variability of response in this age group. The presence of dehydration, especially in younger children, may further influence the variability of response to the drug.
American Society of Health-System Pharmacists 2016; Drug Information 2016. Bethesda, MD. 2016, p. 2971
Loperamide should not be used in the treatment of diarrhea resulting from some infections or in patients with pseudomembranous colitis (e.g., associated with antibiotics). Loperamide is contraindicated in patients with a known hypersensitivity to the drug and in patients in whom constipation must be avoided.
American Society of Health-System Pharmacists 2016; Drug Information 2016. Bethesda, MD. 2016, p. 2971
Patients receiving loperamide should be advised to consult their clinician if the diarrhea persists for longer than 2 days, if symptoms worsen, if abdominal swelling or bulging develops, or if fever develops. For self-medication, loperamide should not be used for longer than 2 days unless directed by a clinician. Loperamide should also not be used for self-medication if diarrhea is accompanied by high fever (greater than 38.3 °C), if blood is present in the stool, or if rash or other allergic reaction to the drug has occurred previously. If a patient is receiving an anti-infective or has a history of liver disease, a physician should be consulted before the drug is used for self-medication.
American Society of Health-System Pharmacists 2016; Drug Information 2016. Bethesda, MD. 2016, p. 2971
For more Drug Warnings (Complete) data for Loperamide (12 total), please visit the HSDB record page.

8 Pharmacology and Biochemistry

8.1 Pharmacodynamics

Loperamide is an anti-diarrheal agent that provides symptomatic relief of diarrhea. 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. Loperamide also increases rectal tone, reduces daily fecal volume, and increases the viscosity and bulk density of feces. It also increases the tone of the anal sphincter, thereby reducing incontinence and urgency. The onset of action is about one hour and the duration of action can be up to three days. While loperamide is a potent mu-opioid receptor agonist, it does not mediate significant analgesic activity at therapeutic and supratherapeutic doses. 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. At very high plasma concentrations, loperamide can interfere with cardiac conduction. Because loperamide inhibits the Na+-gated cardiac channels and ether-a-go-go–related gene potassium channels, 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.

8.2 MeSH Pharmacological Classification

Antidiarrheals
Miscellaneous agents found useful in the symptomatic treatment of diarrhea. They have no effect on the agent(s) that cause diarrhea, but merely alleviate the condition. (See all compounds classified as Antidiarrheals.)

8.3 FDA Pharmacological Classification

FDA UNII
6X9OC3H4II
Active Moiety
LOPERAMIDE
Pharmacological Classes
Established Pharmacologic Class [EPC] - Opioid Agonist
Pharmacological Classes
Mechanisms of Action [MoA] - Opioid Agonists
FDA Pharmacology Summary
Loperamide is an Opioid Agonist. The mechanism of action of loperamide is as an Opioid Agonist.

8.4 ATC Code

S76 | LUXPHARMA | Pharmaceuticals Marketed in Luxembourg | Pharmaceuticals marketed in Luxembourg, as published by d'Gesondheetskeess (CNS, la caisse nationale de sante, www.cns.lu), mapped by name to structures using CompTox by R. Singh et al. (in prep.). List downloaded from https://cns.public.lu/en/legislations/textes-coordonnes/liste-med-comm.html. Dataset DOI:10.5281/zenodo.4587355

A - Alimentary tract and metabolism

A07 - Antidiarrheals, intestinal antiinflammatory/antiinfective agents

A07D - Antipropulsives

A07DA - Antipropulsives

A07DA03 - Loperamide

8.5 Absorption, Distribution and Excretion

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. The drug bioavailability is less than 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.
Route of Elimination
Loperamide and its metabolites in the systemic circulation undergo biliary excretion. Excretion of the unchanged loperamide and its metabolites mainly occurs through the feces. Only 1% of an absorbed dose excreted unchanged in the urine.
Volume of Distribution
Loperamide has a large volume of distribution. Although highly lipophilic, loperamide does not cross the blood-brain barrier and generally acts peripherally.
Tritium-labelled loperamide was administered orally to eight groups of five fasted male Wistar rats (250 +/- 10 g) at a dosage of 1.25 mg/kg. Urine and feces were collected for up to 4 days. The rats were killed at different times from 1 to 96 hours after drug administration in order to examine blood, organs and tissues. In one rat, the bile was cannulated for 48 hours. The radioactive content of each sample was measured and the fractions due to loperamide, metabolites, and volatile radioactivity were determined by the inverse isotope dilution technique and lyophilization. Only 5% of the drug and its metabolites was recovered from the urine, the bulk being excreted with the feces. Drug plasma levels were low at all times. Maximum plasma levels of unchanged loperamide did not exceed 0.22% of the administered dose corresponding to about 75 mg/mL of plasma. The gastrointestinal tract contained about 85% of loperamide 1 hour after dosing. Brain levels were extremely low, never exceeding 22 ng/g brain tissue, or 0.005% of the administered dose. The existence of an enterohepatic shunt was shown, but the uptake of the drug into the general circulation was low. Differentiation between total radioactivity and nonvolatile radioactivity demonstrated that most of the residual organ radioactivity was due to tritiated water.
Health Canada; Product Monograph for Imodium Caplets, Imodium Quick-Dissolve,Imodium Calming Liquid and Imodium Liqui-Gels (Loperamide Hydrochloride), Drug Identification Number (DIN): 02230542 p.22-3 (Date of Revision: November 10, 2011). Available from, as of June 29, 2016: https://webprod5.hc-sc.gc.ca/dpd-bdpp/start-debuter.do?lang=eng
Three male volunteers received orally 2.0 mg of 3H-loperamide (specific activity 64 mCi/mM) in gelatine capsules. Control samples of blood, urine and feces were obtained before administration. Blood was collected on heparin 1, 2, 4, 8, 24, 72 and 168 hours thereafter. Urine was collected for seven days and feces for eight days. The radioactive content of each sample was measured and the fractions due to loperamide, metabolites and volatile radioactivity were determined by the inverse isotope dilution technique and lyophilization. The fate of orally administered 3H-loperamide in man appeared to be similar to that in rats. The peak plasma level of loperamide occurred 4 hours after treatment and was less than 2 ng/mL or about 0.3% of the administered dose. About 1% of the administered dose was excreted unaltered with the urine and 6% as nonvolatile metabolites. About 40% of the administered dose was excreted with the feces, mainly within the first four days; 30% of this amount was due to unchanged drug.
Health Canada; Product Monograph for Imodium Caplets, Imodium Quick-Dissolve,Imodium Calming Liquid and Imodium Liqui-Gels (Loperamide Hydrochloride), Drug Identification Number (DIN): 02230542 p.18 (Date of Revision: November 10, 2011). Available from, as of June 29, 2016: https://webprod5.hc-sc.gc.ca/dpd-bdpp/start-debuter.do?lang=eng
Studies on distribution in rats show a high affinity for the gut wall with a preference for binding to receptors of the longitudinal muscle layer. The plasma protein binding of loperamide is 95%, mainly to albumin. Non-clinical data have shown that loperamide is a P-glycoprotein substrate.
Health Canada; Product Monograph for Imodium Caplets, Imodium Quick-Dissolve,Imodium Calming Liquid and Imodium Liqui-Gels (Loperamide Hydrochloride), Drug Identification Number (DIN): 02230542 p.13 (Date of Revision: November 10, 2011). Available from, as of June 29, 2016: https://webprod5.hc-sc.gc.ca/dpd-bdpp/start-debuter.do?lang=eng
/MILK/ Small amounts of loperamide may appear in human breast milk.
Health Canada; Product Monograph for Imodium Caplets, Imodium Quick-Dissolve,Imodium Calming Liquid and Imodium Liqui-Gels (Loperamide Hydrochloride), Drug Identification Number (DIN): 02230542 p.6 (Date of Revision: November 10, 2011). Available from, as of June 29, 2016: https://webprod5.hc-sc.gc.ca/dpd-bdpp/start-debuter.do?lang=eng
For more Absorption, Distribution and Excretion (Complete) data for Loperamide (8 total), please visit the HSDB record page.

8.6 Metabolism / Metabolites

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. Metabolites of loperamide are pharmacologically inactive.
Loperamide is almost completely extracted by the liver, where it is predominantly metabolized, conjugated and excreted via the bile. Oxidative N-demethylation is the main metabolic pathway for loperamide, and is mediated mainly through CYP3A4 and CYP2C8. Due to this very high first pass effect, plasma concentrations of unchanged drug remain extremely low.
Health Canada; Product Monograph for Imodium Caplets, Imodium Quick-Dissolve,Imodium Calming Liquid and Imodium Liqui-Gels (Loperamide Hydrochloride), Drug Identification Number (DIN): 02230542 p.13 (Date of Revision: November 10, 2011). Available from, as of June 29, 2016: https://webprod5.hc-sc.gc.ca/dpd-bdpp/start-debuter.do?lang=eng
In contrast with the Parkinson's-like effects associated with the mitochondrial neurotoxin N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and the neuroleptic agent haloperidol, there exist no reports on adverse central nervous system (CNS) effects with the structurally related N-substituted-4-arylpiperidin-4-ol derivative and antidiarrheal agent loperamide. Although this difference can be attributed to loperamide's P-glycoprotein substrate properties that prevent it from accessing the brain, an alternative possibility is that loperamide metabolism in humans is different from that of MPTP and haloperidol and does not involve bioactivation to a neurotoxic pyridinium species. In the current study, loperamide bioactivation was examined with particular focus on identification of pyridinium metabolites. A NADPH-dependent disappearance of loperamide was observed in both rat and human liver microsomes (human t(1/2) = 13 min; rat t(1/2) = 22 min). Loperamide metabolism was similar in human and rat and involved N-dealkylation to N-desmethylloperamide (M3) as the principal metabolic fate. Other routes of loperamide biotransformation included N- and C-hydroxylation to the loperamide-N-oxide (M4) and carbinolamide (M2) metabolites, respectively. Furthermore, the formation of an additional metabolite (M5) was also discernible in human and rat liver microsomes. The structure of M5 was assigned to the pyridinium species (LPP(+)) based on comparison of the liquid chromatography/tandem mass spectrometry characteristics to the pyridinium obtained from loperamide via a chemical reaction. Loperamide metabolism in human microsomes was sensitive to ketoconazole and bupropion treatment, suggesting P4503A4 and -2B6 involvement. Recombinant P4503A4 catalyzed all of the loperamide biotransformation pathways in human liver microsomes, whereas P4502B6 was only responsible for N-dealkylation and N-oxidation routes. The wide safety margin of loperamide (compared with MPTP and haloperidol) despite metabolism to a potentially neurotoxic pyridinium species likely stems from a combination of factors that include a therapeutic regimen normally restricted to a few days and the fact that loperamide and perhaps LPP(+) are P-glycoprotein substrates and are denied entry into the CNS. The differences in safety profile of haloperidol and loperamide despite a common bioactivation event supports the notion that not all compounds undergoing bioactivation in vitro will necessarily elicit a toxicological response in vivo.
Kalgutkar AS, Nguyen HT; Drug Metab Dispos 32 (9): 943-52 (2004)
Loperamide has known human metabolites that include N-Desmethyloperamide.
S73 | METXBIODB | Metabolite Reaction Database from BioTransformer | DOI:10.5281/zenodo.4056560

8.7 Biological Half-Life

The apparent elimination half-life of loperamide is 10.8 hours with a range of 9.1 to 14.4 hours.
The apparent elimination half-life of loperamide in healthy adults is 10.8 hours (range 9.1-14.4 hours).
American Society of Health-System Pharmacists 2016; Drug Information 2016. Bethesda, MD. 2016

8.8 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. Loperamide acts on the mu-opioid receptor expressed on the circular and longitudinal intestinal muscle. Receptor binding leads to the recruitment of G-protein receptor kinases and the activation of downstream molecular cascades that inhibit enteric nerve activity. 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. Loperamide inhibits the release of acetylcholine and prostaglandins, thereby reducing propulsive peristalsis and increasing intestinal transit time. Loperamide stimulates the intestinal absorption of water and electrolytes by inhibiting calmodulin. Loperamide can bind to and hyperpolarize submucosal secretomotor neurons, promoting dry, hard stools.
... The present study investigates the mechanism of the central analgesic effect of loperamide. Adult male Sprague-Dawley rats were subjected to surgery for catheter placement. Following baseline testing, different groups of rats were administered fixed intrathecal doses (1 ug, 3 ug, 10 ug and 30 ug) of loperamide and morphine. Analgesia was compared employing Hargreaves paw withdrawal apparatus at 15 min, 30 min, 60 min, 90 min and 120 min. Additionally, CTOP, a specific mu-opioid receptor antagonist was co-administered with loperamide to examine the mu-opioid receptor mediated loperamide analgesia. Furthermore, nefiracetam, a calcium channel opener, was co-administered with loperamide or morphine to evaluate the involvement of Ca(2+) channels in loperamide showed an analgesic effect which was comparable to morphine. However, loperamide produced longer analgesia and the analgesic effect was significantly better at 42 hr and 49 hr compared to morphine. CTOP completely reversed loperamide analgesia. Though nefiracetam significantly reversed loperamide analgesia, it did not have any effect on morphine induced analgesia. Our findings suggest that loperamide administered intrathecally produces analgesia which is mediated through mu-opioid receptor and subsequent blockade of downstream calcium channels.
Kumar R et al; Eur J Pharmacol 696 (1-3): 77-82 (2012)
The effects of the antidiarrheal agent loperamide on high-voltage-activated (HVA) calcium channel activity and excitatory amino acid-evoked responses in two preparations of cultured hippocampal pyramidal neurons were examined. In rat hippocampal neurons loaded with the calcium-sensitive dye fura-2, rises in intracellular free calcium concentration ([Ca2+]i) evoked by transient exposure to 50 mM K(+)-containing medium [high extracellular potassium concentration ([K+]o)] were mediated by Ca2+ flux largely through nifedipine-sensitive Ca2+ channels, with smaller contributions from omega-conotoxin GVIA (omega-CgTx)-sensitive Ca2+ channels and channels insensitive to both nifedipine and omega-CgTx. Loperamide reversibly blocked rises in [Ca2+]i evoked by high [K+]o in a concentration-dependent manner, with an IC50 of 0.9 +/- 0.2 microM. At the highest concentration tested (50 microM), loperamide eliminated rises in [Ca2+]i evoked by high [K+]o, a result otherwise achieved only in Ca(2+)-free medium or by the combined application of nifedipine, omega-CgTx, and funnel web spider venom to Ca(2+)-containing medium. The action of loperamide was neither naloxone sensitive nor mimicked by morphine and was seen at concentrations substantially less than those required to block influx of Ca2+ through the N-methyl-D-aspartate (NMDA) receptor-operated ionophore. Similar results were obtained in cultured mouse hippocampal pyramidal neurons under whole-cell voltage clamp. Voltage-activated Ca2+ channel currents carried by barium ions (IBa) could be discriminated pharmacologically into nifedipine-sensitive (L-type) and nifedipine-resistant, omega-CgTx-sensitive (N-type) components. Loperamide (0.1-50 uM) produced a concentration-dependent reduction of the peak IBa with an IC50 value of 2.5 +/- 0.4 uM and, at the highest concentration tested, could fully block IBa in the absence of any other pharmacological agent. The loperamide-induced block was rapid in onset and offset, was fully reversible, and did not appear to be related to the known calmodulin antagonist actions of loperamide. The current-voltage characteristics of the whole-cell IBa were unaffected by loperamide and the block was not voltage dependent. Loperamide also attenuated NMDA-evoked currents recorded at a membrane potential of -60 mV, with an IC50 of 73 +/- 7 uM. The block of NMDA-evoked currents was not competitive in nature, was not reversed by elevation of the extracellular glycine or spermine concentration, and was not affected by changes in the membrane holding potential. Steady state currents evoked by kainate and DL-alpha-amino-3-hydroxy-5-methylisoxazolepropionic acid were, in contrast, relatively unaffected by 100 microM loperamide.
Church J et al; Mol Pharmacol 45 (4): 747-57 (1994)
The intravenous injection of loperamide induced an immediate fall in blood pressure and heart rate in anesthetized rats. Both effects were inhibited by the opiate antagonists naloxone and MRZ 2266 BS. Bilateral vagotomy also inhibited both effects whereas atropine only reduced the bradycardia, but the combination of atropine and tertatolol suppressed the bradycardia. A high dose of loperamide induced bradycardia in pithed rats. This effect was prevented by MRZ 2266 BS but not by naloxone. It is concluded that loperamide can elicit a vagally mediated reflex involving vagal and sympathetic mechanisms and could stimulate cardiac opiate receptors, probably kappa, both effects leading to bradycardia.
Gautret B, Schmitt H; Eur J Pharmacol 107 (2): 157-60 (1985)
Motility in the gut is the result of cholinergic and noncholinergic biphasic stimulation of the intestinal musculature. The cholinergic mediator, acetylcholine (ACh), is responsible for the first phase of peristalsis, while prostaglandins (PG) are thought to mediate the second phase. Loperamide has been shown to inhibit release of both ACh and PG from isolated guinea pig ileum, as well as directly block the action of PG on smooth muscle preparations from rats. The net result is a reduction in the number of peristaltic waves, the fluid expelled by each wave, and overall gut motility. Loperamide produces a sustained inhibition of the peristaltic activity of the guinea pig ileum in vitro at doses as low as 0.005 mg/L. The inhibitory effects are dose-related, the activity of both the longitudinal and circular muscles being affected. At dose levels inhibiting peristaltic activity, loperamide antagonizes the spasmogenic effects of electrical- and nicotine-induced stimulation of this preparation. As well, the angiotensin-5- hydroxytryptamine-, bradykinin-barium chloride- and histamine-induced contractions of the guinea pig ileum preparation are inhibited by doses of 0.14 mg/L or more. On the other hand, loperamide is inactive against 5-hydroxytryptamine on the rat fundus, epinephrine on the rabbit spleen, acetylcholine on the rabbit duodenum and isoproterenol on the hen rectal caecum preparations at dose levels of up to 10 mg/L. A moderate negative inotropic effect is produced on the cat papillary muscle at 3 and 10 mg/L, and a moderate negative chronotropic effect is produced on the guinea pig atrium at 0.16 mg/L. This antagonism is thought to be unspecific.
Health Canada; Product Monograph for Imodium Caplets, Imodium Quick-Dissolve,Imodium Calming Liquid and Imodium Liqui-Gels (Loperamide Hydrochloride), Drug Identification Number (DIN): 02230542 p.21 (Date of Revision: November 10, 2011). Available from, as of June 29, 2016: https://webprod5.hc-sc.gc.ca/dpd-bdpp/start-debuter.do?lang=eng

8.9 Human Metabolite Information

8.9.1 Cellular Locations

Membrane

8.10 Biochemical Reactions

8.11 Transformations

9 Use and Manufacturing

9.1 Uses

Antidiarrheals
National Library of Medicine's Medical Subject Headings. Loperamide. Online file (MeSH, 2016). Available from, as of June 24, 2016: https://www.nlm.nih.gov/mesh/2016/mesh_browser/MBrowser.html
MEDICATION
MEDICATION (VET)

<b>Use (kg; approx.) in Germany (2009):</b> >250

<b>Use (kg) in USA (2002):</b> 20600

<b>Use (kg) in France (2004):</b> 318

<b>Consumption (g per capita; approx.) in Germany (2009):</b> 0.00305

<b>Consumption (g per capita) in the USA (2002):</b> 0.073

<b>Consumption (g per capita) in France (2004):</b> 0.00526

<b>Calculated removal (%):</b> 81.9

9.1.1 Use Classification

Pharmaceuticals
S72 | NTUPHTW | Pharmaceutically Active Substances from National Taiwan University | DOI:10.5281/zenodo.3955664

9.2 Methods of Manufacturing

4-Bromo-2,2-diphenylbutyric acid is converted in a series of reactions to dimethyl(tetrahydro-3,3-diphenyl-2-furylidene) ammonium bromide, which is reacted with p-chlorophenyl-4-piperidinol to produce loperamide.
Troy, D.B. (Ed); Remmington The Science and Practice of Pharmacy. 21 st Edition. Lippincott Williams & Williams, Philadelphia, PA 2005, p. 1309
Preparation: Janssen et al., France patent 2100711; eidem, United States of American patent 3714159 (1972, 1973 to Janssen).
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 1035

9.3 Formulations / Preparations

Table: Loperamide Hydrochloride Preparations
Route of Administration
Oral
Dosage Form
Solution
Strength
1 mg/5 mL
Brand or Generic Form (Manufacturer)
Anti-diarrheal Formula (Teva)
Route of Administration
Oral
Dosage Form
Solution
Strength
1 mg/5 mL
Brand or Generic Form (Manufacturer)
Imodium A-D (McNeil)
Route of Administration
Oral
Dosage Form
Solution
Strength
1 mg/5 mL
Brand or Generic Form (Manufacturer)
Loperamide Hydrochloride Oral Solution (Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
Route of Administration
Oral
Dosage Form
Tablets
Strength
2 mg
Brand or Generic Form (Manufacturer)
Anti-diarrheal Formula Caplets (Teva)
Route of Administration
Oral
Dosage Form
Tablets
Strength
2 mg
Brand or Generic Form (Manufacturer)
Imodium A-D Caplets, scored (McNeil)
Route of Administration
Oral
Dosage Form
Tablets
Strength
2 mg
Brand or Generic Form (Manufacturer)
Loperamide Hydrochloride Tablets (Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
American Society of Health-System Pharmacists 2016; Drug Information 2016. Bethesda, MD. 2016, p. 2971
Table: Loperamide Hydrochloride Combinations Preparations
Route of Administration
Oral
Dosage Form
Tablets
Strength
2 mg with Simethicone 125 mg
Brand or Generic Form (Manufacturer)
Imodium Advanced Caplets (McNeil)
Route of Administration
Oral
Dosage Form
Tablets, chewable
Strength
2 mg with Simethicone 125 mg
Brand or Generic Form (Manufacturer)
Imodium Advanced Chewable Tablets (McNeil)
Route of Administration
Oral
Dosage Form
Tablets, chewable
Strength
2 mg with Simethicone 125 mg
Brand or Generic Form (Manufacturer)
Loperamide Hydrochloride and Simethicone Chewable Tablets Laperamide Hydrochloride Tablets (Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
American Society of Health-System Pharmacists 2016; Drug Information 2016. Bethesda, MD. 2016, p. 2971

10 Identification

10.1 Clinical Laboratory Methods

A liquid chromatographic mass spectrometric (LC/MS/MS) method has been developed for the determination of loperamide in whole blood and other biological specimens. The procedure involves liquid-liquid extraction of loperamide, desmethylloperamide and methadone-D3 (internal standard) with butyl acetate. Confirmation and quantification was done by positive electrospray ionization with a triple quadrupole mass spectrometer operating in multiple reaction-monitoring (MRM) mode. Two MRM transitions of each compound were established and identification criteria were set up based on the ratio of the responses between the two MRM transitions of each compound. The standard curves were linear over a working range of 0.1-500 ug/kg for all transitions. The limit of quantification was 0.1 ug/kg in whole blood. The repeatability and reproducibility within the laboratory expressed by relative standard deviation were less than 5 and 11%, respectively, and the accuracy was better than 9%. The method was developed to examine a feces sample from a child whose mother was suspected of Munchausen syndrome by proxy and it proved to be suitable for forensic cases being simple, selective and reproducible. The method was also applied for a case investigation involving a overdose of loperamide.
Johansen SS, Jensen JL; J Chromatogr B Analyt Technol Biomed Life Sci 811 (1): 31-6 (2004)

11 Safety and Hazards

11.1 Hazards Identification

11.1.1 GHS Classification

Pictogram(s)
Acute Toxic
Signal
Danger
GHS Hazard Statements
H301 (100%): Toxic if swallowed [Danger Acute toxicity, oral]
Precautionary Statement Codes

P264, P270, P301+P316, P321, P330, P405, and P501

(The corresponding statement to each P-code can be found at the GHS Classification page.)

ECHA C&L Notifications Summary

Aggregated GHS information provided per 7 reports by companies from 1 notifications to the ECHA C&L Inventory.

Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown.

11.1.2 Hazard Classes and Categories

Acute Tox. 3 (100%)

11.2 Fire Fighting

11.2.1 Fire Fighting Procedures

Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide. /Loperamide hydrochloride/
Sigma-Aldrich; Safety Data Sheet for Loperamide Hydrochloride. Product Number: N4762, Version 5.2 (Revision Date 06/21/2014). Available from, as of June 29, 2016: https://www.sigmaaldrich.com/safety-center.html
Advice for firefighters: Wear self-contained breathing apparatus for firefighting if necessary. /Loperamide hydrochloride/
Sigma-Aldrich; Safety Data Sheet for Loperamide Hydrochloride. Product Number: N4762, Version 5.2 (Revision Date 06/21/2014). Available from, as of June 29, 2016: https://www.sigmaaldrich.com/safety-center.html

11.3 Accidental Release Measures

11.3.1 Cleanup Methods

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Wear respiratory protection. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Evacuate personnel to safe areas. Avoid breathing dust. Environmental precautions: Prevent further leakage or spillage if safe to do so. Do not let product enter drains. Methods and materials for containment and cleaning up: Pick up and arrange disposal without creating dust. Sweep up and shovel. Keep in suitable, closed containers for disposal. /Loperamide hydrochloride/
Sigma-Aldrich; Safety Data Sheet for Loperamide Hydrochloride. Product Number: N4762, Version 5.2 (Revision Date 06/21/2014). Available from, as of June 29, 2016: https://www.sigmaaldrich.com/safety-center.html

11.3.2 Disposal Methods

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.
Product: Offer surplus and non-recyclable solutions to a licensed disposal company. Contact a licensed professional waste disposal service to dispose of this material. Dissolve or mix the material with a combustible solvent and burn in a chemical incinerator equipped with an afterburner and scrubber; Contaminated packaging: Dispose of as unused product. /Loperamide hydrochloride/
Sigma-Aldrich; Safety Data Sheet for Loperamide Hydrochloride. Product Number: N4762, Version 5.2 (Revision Date 06/21/2014). Available from, as of June 29, 2016: https://www.sigmaaldrich.com/safety-center.html

11.3.3 Preventive Measures

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Wear respiratory protection. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Evacuate personnel to safe areas. Avoid breathing dust. Environmental precautions: Prevent further leakage or spillage if safe to do so. Do not let product enter drains. ... /Loperamide hydrochloride/
Sigma-Aldrich; Safety Data Sheet for Loperamide Hydrochloride. Product Number: N4762, Version 5.2 (Revision Date 06/21/2014). Available from, as of June 29, 2016: https://www.sigmaaldrich.com/safety-center.html
Precautions for safe handling: Avoid contact with skin and eyes. Avoid formation of dust and aerosols. Provide appropriate exhaust ventilation at places where dust is formed. /Loperamide hydrochloride/
Sigma-Aldrich; Safety Data Sheet for Loperamide Hydrochloride. Product Number: N4762, Version 5.2 (Revision Date 06/21/2014). Available from, as of June 29, 2016: https://www.sigmaaldrich.com/safety-center.html
Appropriate engineering controls: Avoid contact with skin, eyes and clothing. Wash hands before breaks and immediately after handling the product. /Loperamide hydrochloride/
Sigma-Aldrich; Safety Data Sheet for Loperamide Hydrochloride. Product Number: N4762, Version 5.2 (Revision Date 06/21/2014). Available from, as of June 29, 2016: https://www.sigmaaldrich.com/safety-center.html
Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands. /Loperamide hydrochloride/
Sigma-Aldrich; Safety Data Sheet for Loperamide Hydrochloride. Product Number: N4762, Version 5.2 (Revision Date 06/21/2014). Available from, as of June 29, 2016: https://www.sigmaaldrich.com/safety-center.html
SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker.

11.4 Handling and Storage

11.4.1 Storage Conditions

Keep container tightly closed in a dry and well-ventilated place. Light sensitive. /Loperamide hydrochloride/
Sigma-Aldrich; Safety Data Sheet for Loperamide Hydrochloride. Product Number: N4762, Version 5.2 (Revision Date 06/21/2014). Available from, as of June 29, 2016: https://www.sigmaaldrich.com/safety-center.html

11.5 Exposure Control and Personal Protection

11.5.1 Personal Protective Equipment (PPE)

Eye/face protection: Safety glasses with side-shields conforming to EN166. Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU). /Loperamide hydrochloride/
Sigma-Aldrich; Safety Data Sheet for Loperamide Hydrochloride. Product Number: N4762, Version 5.2 (Revision Date 06/21/2014). Available from, as of June 29, 2016: https://www.sigmaaldrich.com/safety-center.html
Skin protection: Handle with gloves. /Loperamide hydrochloride/
Sigma-Aldrich; Safety Data Sheet for Loperamide Hydrochloride. Product Number: N4762, Version 5.2 (Revision Date 06/21/2014). Available from, as of June 29, 2016: https://www.sigmaaldrich.com/safety-center.html
Body Protection: Complete suit protecting against chemicals. The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace. /Loperamide hydrochloride/
Sigma-Aldrich; Safety Data Sheet for Loperamide Hydrochloride. Product Number: N4762, Version 5.2 (Revision Date 06/21/2014). Available from, as of June 29, 2016: https://www.sigmaaldrich.com/safety-center.html
Respiratory protection: For nuisance exposures use type P95 (US) or type P1 (EU EN 143) particle respirator. For higher level protection use type OV/AG/P99 (US) or type ABEK-P2 (EU EN 143) respirator cartridges. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU). /Loperamide hydrochloride/
Sigma-Aldrich; Safety Data Sheet for Loperamide Hydrochloride. Product Number: N4762, Version 5.2 (Revision Date 06/21/2014). Available from, as of June 29, 2016: https://www.sigmaaldrich.com/safety-center.html

11.6 Stability and Reactivity

11.6.1 Hazardous Reactivities and Incompatibilities

Incompatible materials: Strong oxidizing agents /Loperamide hydrochloride/
Sigma-Aldrich; Safety Data Sheet for Loperamide Hydrochloride. Product Number: N4762, Version 5.2 (Revision Date 06/21/2014). Available from, as of June 29, 2016: https://www.sigmaaldrich.com/safety-center.html

11.7 Regulatory Information

REACH Registered Substance

11.7.1 FDA Requirements

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including loperamide hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Loperamide hydrochloride/
DHHS/FDA; Electronic Orange Book-Approved Drug Products with Therapeutic Equivalence Evaluations. Available from, as of July 6, 2016: https://www.fda.gov/cder/ob/
The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed over-the-counter drug products, including loperamide hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Loperamide hydrochloride/
DHHS/FDA; Electronic Orange Book-Approved Drug Products with Therapeutic Equivalence Evaluations. Available from, as of July 6, 2016: https://www.fda.gov/cder/ob/

11.8 Other Safety Information

Chemical Assessment

IMAP assessments - 1-Piperidinebutanamide, 4-(4-chlorophenyl)-4-hydroxy-N,N-dimethyl-.alpha.,.alpha.-diphenyl-: Environment tier I assessment

IMAP assessments - 1-Piperidinebutanamide, 4-(4-chlorophenyl)-4-hydroxy-N,N-dimethyl-.alpha.,.alpha.-diphenyl-: Human health tier I assessment

11.8.1 Toxic Combustion Products

Special hazards arising from the substance or mixture: Carbon oxides, Nitrogen oxides (NOx), Hydrogen chloride gas /Loperamide hydrochloride/
Sigma-Aldrich; Safety Data Sheet for Loperamide Hydrochloride. Product Number: N4762, Version 5.2 (Revision Date 06/21/2014). Available from, as of June 29, 2016: https://www.sigmaaldrich.com/safety-center.html

12 Toxicity

12.1 Toxicological Information

12.1.1 Toxicity Summary

IDENTIFICATION AND USE: Loperamide is a solid. Loperamide is used in the control and symptomatic relief of acute nonspecific diarrhea and of chronic diarrhea associated with inflammatory bowel disease. HUMAN EXPOSURE AND TOXICITY: Loperamide is an over-the-counter antidiarrheal with mu-opioid agonist activity. Central nervous system opioid effects are not observed after therapeutic oral dosing because of poor bioavailability and minimal central nervous system penetration. However, central nervous system opioid effects do occur after supratherapeutic oral doses. Oral loperamide abuse as an opioid substitute has been seen among patients attempting to self-treat their opioid addiction. Ventricular dysrhythmias and prolongation of the QRS duration and QTc interval have been reported after oral loperamide abuse. In postmarketing experiences, paralytic ileus associated with abdominal distention has been reported rarely. Most of these cases occurred in patients with acute dysentery, following overdosage of the drug, or in children younger than 2 years of age. ANIMAL STUDIES: Loperamide administration significantly suppressed foraging behavior in rats and reduced their body weight. The intravenous injection of loperamide induced an immediate fall in blood pressure and heart rate in anesthetized rats. In a study in rats using loperamide dosages up to 133 times the maximum human dosage (on a mg/kg basis) for 18 months, there was no evidence of carcinogenicity. Beagle dogs were given loperamide in gelatin capsules at 5.0, 1.25 and 0.31 mg/kg six days a week for 12 months. Some depression was seen during the first week of drug administration at 1.25 and 5 mg/kg. Behavior and appearance were normal during the rest of the experiment, except that hemorrhagic stools were seen from time to time at 5 mg/kg and soft stools at 0.31 and 1.25 mg/kg, especially during the first 6 weeks of drug administration. Pregnant primiparous female rats were given loperamide in their diet at 40, 10 and 2.5 mg/100 g of food from day 6 through day 15 of pregnancy. On day 22, fetuses were delivered by caesarean section. At 40 mg/100 g food, only 1 female out of 20 became pregnant. There was no significant difference between the control group and the 2.5 and 10 mg/100 g food-dosed groups in pregnancy rate; number of implantations per dam; litter size, percentage of live, dead and resorbed fetuses; distribution of live, dead and resorbed fetuses in the left and right uterine horns; and body weight of live young. No macroscopic, visceral, or skeletal malformations were seen. Results of in vivo and in vitro studies carried out indicated that loperamide is not genotoxic.

12.1.2 USGS Health-Based Screening Levels for Evaluating Water-Quality

Chemical
Loperamide
Chemical Classes
Pharmaceutical
Reference
Smith, C.D. and Nowell, L.H., 2024. Health-Based Screening Levels for evaluating water-quality data (3rd ed.). DOI:10.5066/F71C1TWP

12.1.3 Hepatotoxicity

As with most opiates in current use, therapy with loperamide has not been linked to serum enzyme elevations. There have been no convincing cases of idiosyncratic acute, clinically apparent liver injury attributed to either agent. The reason for its lack of hepatotoxicity may relate to the low doses used and lack of significant systemic absorption. What loperamide is absorbed is metabolized in the liver.

References on the safety and potential hepatotoxicity of loperamide are given in the overview section of the Opioids. Last updated: 20 May 2019

Drug Class: Gastrointestinal Agents; Opioids

12.1.4 Drug Induced Liver Injury

Compound
loperamide
DILI Annotation
No-DILI-Concern
Label Section
No match
References

M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. FDA-Approved Drug Labeling for the Study of Drug-Induced Liver Injury, Drug Discovery Today, 16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007

M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank: the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans. Drug Discov Today 2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015

12.1.5 Effects During Pregnancy and Lactation

◉ Summary of Use during Lactation

The amount of loperamide that enters milk from a prodrug of loperamide is minimal. Use of loperamide during breastfeeding is unlikely to affect the infant with standard doses.

◉ Effects in Breastfed Infants

Relevant published information was not found as of the revision date.

◉ Effects on Lactation and Breastmilk

Relevant published information was not found as of the revision date.

12.1.6 Acute Effects

12.1.7 Interactions

Non-clinical data have shown that loperamide is a P-glycoprotein substrate. Concomitant administration of loperamide (16 mg single dose) with quinidine, or ritonavir, which are both Pglycoprotein inhibitors, resulted in a 2 to 3-fold increase in loperamide plasma levels. The clinical relevance of this pharmacokinetic interaction with P-glycoprotein inhibitors, when loperamide is given at recommended dosages is unknown.
Health Canada; Product Monograph for Imodium Caplets, Imodium Quick-Dissolve,Imodium Calming Liquid and Imodium Liqui-Gels (Loperamide Hydrochloride), Drug Identification Number (DIN): 02230542 p.10 (Date of Revision: November 10, 2011). Available from, as of June 29, 2016: https://webprod5.hc-sc.gc.ca/dpd-bdpp/start-debuter.do?lang=eng
Concomitant treatment /of loperamide/ with oral desmopressin resulted in a 3-fold increase of desmopressin plasma concentrations, presumably due to slower gastrointestinal motility.
Health Canada; Product Monograph for Imodium Caplets, Imodium Quick-Dissolve,Imodium Calming Liquid and Imodium Liqui-Gels (Loperamide Hydrochloride), Drug Identification Number (DIN): 02230542 p.10 (Date of Revision: November 10, 2011). Available from, as of June 29, 2016: https://webprod5.hc-sc.gc.ca/dpd-bdpp/start-debuter.do?lang=eng
Loperamide is biotransformed in vitro by the cytochromes P450 (CYP) 2C8 and 3A4 and is a substrate of the P-glycoprotein efflux transporter. Our aim was to investigate the effects of itraconazole, an inhibitor of CYP3A4 and P-glycoprotein, and gemfibrozil, an inhibitor of CYP2C8, on the pharmacokinetics of loperamide. In a randomized crossover study with 4 phases, 12 healthy volunteers took 100 mg itraconazole (first dose 200 mg), 600 mg gemfibrozil, both itraconazole and gemfibrozil, or placebo, twice daily for 5 days. On day 3, they ingested a single 4-mg dose of loperamide. Loperamide and N-desmethylloperamide concentrations in plasma were measured for up to 72 hr and in urine for up to 48 hr. Possible central nervous system effects of loperamide were assessed by the Digit Symbol Substitution Test and by subjective drowsiness. Itraconazole raised the peak plasma loperamide concentration (Cmax) 2.9-fold (range, 1.2-5.0; p < 0.001) and the total area under the plasma loperamide concentration-time curve (AUC(0-infinity)) 3.8-fold (1.4-6.6; p < 0.001) and prolonged the elimination half-life (t(1/2)) of loperamide from 11.9 to 18.7 hr (p < 0.001). Gemfibrozil raised the Cmax of loperamide 1.6-fold (0.9-3.2; P < 0.05) and its AUC(0-infinity) 2.2-fold (1.0-3.7; P < 0.05) and prolonged its t(1/2) to 16.7 hr (P < 0.01). The combination of itraconazole and gemfibrozil raised the Cmax of loperamide 4.2-fold (1.5-8.7; P < 0.001) and its AUC(0-infinity) 12.6-fold (4.3-21.8; P < 0.001) and prolonged the t(1/2) of loperamide to 36.9 hr (p < 0.001). The amount of loperamide excreted into urine within 48 hr was increased 3.0-fold, 1.4-fold and 5.3-fold by itraconazole, gemfibrozil and their combination, respectively (p < 0.05). Itraconazole, gemfibrozil and their combination reduced the plasma AUC(0-72) ratio of N-desmethylloperamide to loperamide by 65%, 46% and 88%, respectively (p < 0.001). No significant differences were seen in the Digit Symbol Substitution Test or subjective drowsiness between the phases. Itraconazole, gemfibrozil and their combination markedly raise the plasma concentrations of loperamide. Although not seen in the psychomotor tests used, an increased risk of adverse effects should be considered during concomitant use of loperamide with itraconazole, gemfibrozil and especially their combination.
Niemi M et al; Eur J Clin Pharmacol 62 (6): 463-72 (2006)

12.1.8 Antidote and Emergency Treatment

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/
Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous Materials Exposure. 3rd revised edition, Elsevier Mosby, St. Louis, MO 2007, p. 160
/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/
Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous Materials Exposure. 3rd revised edition, Elsevier Mosby, St. Louis, MO 2007, p. 160
/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/
Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous Materials Exposure. 3rd revised edition, Elsevier Mosby, St. Louis, MO 2007, p. 160-1
Treatment is symptomatic and supportive. Appropriate standard methods of gastrointestinal decontamination may be employed. Activated charcoal administered in appropriate dosages, promptly after ingestion of loperamide hydrochloride can reduce the amount of drug which is absorbed into the systemic circulation by as much as nine fold. In the event of overdosage, patients should be monitored for signs of CNS depression for at least 48 hours. If symptoms of overdose occur, naloxone can be given as an antidote. Since the duration of action of Imodium is longer than that of naloxone (1 to 3 hours), repeated treatment with naloxone might be indicated. If responsive to naloxone, vital signs must be monitored carefully for recurrence of symptoms of drug overdose for at least 48 hours after the last dose of naloxone. Since relatively little drug is excreted in the urine, forced diuresis is not expected to be effective for Imodium overdosage.
Health Canada; Product Monograph for Imodium Caplets, Imodium Quick-Dissolve,Imodium Calming Liquid and Imodium Liqui-Gels (Loperamide Hydrochloride), Drug Identification Number (DIN): 02230542 p.12-3 (Date of Revision: November 10, 2011). Available from, as of June 29, 2016: https://webprod5.hc-sc.gc.ca/dpd-bdpp/start-debuter.do?lang=eng

12.1.9 Human Toxicity Excerpts

/HUMAN EXPOSURE STUDIES/ This crossover, double-blind study investigated the effects of single oral doses of the prodrug loperamide oxide, which is reduced gradually to loperamide in the intestine, and loperamide on jejunal motor activity in 12 fasting healthy men. Five minutes after a phase III of the migrating motor complex (MMC), 2 mg loperamide oxide, 4 mg loperamide oxide, 4 mg loperamide, or placebo were administered. Thereafter, motor activity 10-30 cm abroad the ligament of Treitz was recorded with five catheter orifices at 3-cm intervals over 4 hr. Number of contractions and area under curve increased significantly with 4 mg loperamide and 4 mg loperamide oxide, the increases with loperamide oxide occurring more gradually. Placebo and 2 mg loperamide oxide had no discernible effects. With both 4 mg loperamide and 4 mg loperamide oxide, phase I of the MMC was slightly prolonged and phase II and the time from drug administration to the onset of the first phase III slightly shortened. The percentage of aborally propagated contractions in phase II increased with all active treatments, whereas the occurrence of phases III was not altered.
Stacher G et al; Dig Dis Sci 37 (2): 198-204 (1992)
/HUMAN EXPOSURE STUDIES/ Loperamide (LOP) is an anti-diarrheal agent which is thought to act largely by slowing transit with an uncertain effect on the fluid content of the small and large bowel in humans. Adding simethicone (SIM) to LOP improves its efficacy, but the mechanism of interaction is unclear. Novel MRI techniques to assess small bowel water content (SBWC) have shown that mannitol solutions markedly increase SBWC and can be used as a model of diarrhea. We aimed to use quantitative MRI techniques to compare the actions in the gut of LOP and LOP + SIM in a model of secretory diarrhoea using mannitol. A total of 18 healthy volunteers ingested capsules containing placebo (PLA) or 12 mg LOP or 12 mg LOP + 125 mg SIM. After 100 min they were given a drink containing 5% mannitol in 350 mL of water. They underwent baseline fasting and postprandial serial MRI scans at 45 min intervals for 4.5 h after ingesting the drink. A range of MRI sequences was acquired to image the gut. LOP and LOP + SIM significantly accelerated gastric emptying (p < 0.03) and reduced SBWC during the late phase (135-270 min after mannitol ingestion), p < 0.009, while delaying arrival of fluid in the ascending colon (AC). The relaxation time T2 of the contents of the AC was reduced by both drugs (p < 0.0001). LOP and LOP + SIM accelerate gastric emptying, but reduce small bowel water content which may contribute to the delay in oral-caecal transit and overall anti-diarrheal effect.
Placidi E et al; Aliment Pharmacol Ther 36 (1): 64-73 (2012)
/HUMAN EXPOSURE STUDIES/ Previous work in our laboratory has found that mild physical activity accelerates mouth-to-large intestinal transit of lactulose in a mixed liquid meal. Because loperamide is commonly used as an antidiarrheal agent, we wondered if it would blunt the orocecal transit acceleration provoked by mild exercise. We investigated this equation in 12 healthy persons by comparing orocolonic liquid transit at rest and in mild exercise. Each subject ingested 8 mg loperamide 1 hr prior to study under both resting and exercise conditions. With loperamide treatment, exercise (walking at 5.6 km/hr) failed to hasten increased H2 excretion (mean transit time 72 +/- 12 min at rest, 90 +/- 15 min in exercise; p = NS). This result contrasts sharply with previously reported controls: loperamide completely abolished exercise-induced orocecal transit acceleration (-23 +/- 5 min in controls; +18 +/- 13 min with loperamide; p < 0.05). Compared with these same controls, resting transit was not significantly slowed by the drug, while transit in exercise was retarded (64 +/- 5 min in controls, 90 +/- 15 min with loperamide; p = 0.06). Loperamide left unchanged the heart rate and oxygen uptake rises associated with exercise. In summary, by showing that loperamide blocks an exercise effect on the upper gut, these results suggest that the drug might prove effective in treating some gut symptoms induced by physical activity.
Keeling WF et al; Dig Dis Sci 38 (10): 1783-7 (1993)
/SIGNS AND SYMPTOMS/ In cases of overdose (including relative overdose due to hepatic dysfunction), central nervous system depression (stupor, coordination abnormality, somnolence, miosis, muscular hypertonia, respiratory depression), urinary retention and ileus may occur. Children may be more sensitive to CNS effects than adults.
Health Canada; Product Monograph for Imodium Caplets, Imodium Quick-Dissolve,Imodium Calming Liquid and Imodium Liqui-Gels (Loperamide Hydrochloride), Drug Identification Number (DIN): 02230542 p.12 (Date of Revision: November 10, 2011). Available from, as of June 29, 2016: https://webprod5.hc-sc.gc.ca/dpd-bdpp/start-debuter.do?lang=eng
For more Human Toxicity Excerpts (Complete) data for Loperamide (29 total), please visit the HSDB record page.

12.1.10 Non-Human Toxicity Excerpts

/LABORATORY ANIMALS: Acute Exposure/ The intravenous injection of loperamide induced an immediate fall in blood pressure and heart rate in anesthetized rats. Both effects were inhibited by the opiate antagonists naloxone and MRZ 2266 BS. Bilateral vagotomy also inhibited both effects whereas atropine only reduced the bradycardia, but the combination of atropine and tertatolol suppressed the bradycardia. A high dose of loperamide induced bradycardia in pithed rats. This effect was prevented by MRZ 2266 BS but not by naloxone. It is concluded that loperamide can elicit a vagally mediated reflex involving vagal and sympathetic mechanisms and could stimulate cardiac opiate receptors, probably kappa, both effects leading to bradycardia.
Gautret B, Schmitt H; Eur J Pharmacol 107 (2): 157-60 (1985)
/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ Wistar rats (10 males and 10 females per dose group) were given loperamide in their diet at 40, 10 and 2.5 mg/100 g of food seven days a week for 15 weeks. Control animals received diet only. No drug-induced mortality was observed. Health, behavior and appearance were normal in all groups, except that the 40 mg/100 g food-dosed animals showed a swollen abdomen during the first four weeks. No effects could be detected on hemograms, serum analyses and urinalyses except a decrease of creatinine in the dosed animals. Weight gain and food consumption were lower in the 40 mg/100 g food-dosed animals. At this 40 mg/100 g food dose, some minor macroscopic and microscopic changes are probably related to reduced food consumption.
Health Canada; Product Monograph for Imodium Caplets, Imodium Quick-Dissolve,Imodium Calming Liquid and Imodium Liqui-Gels (Loperamide Hydrochloride), Drug Identification Number (DIN): 02230542 p.24 (Date of Revision: November 10, 2011). Available from, as of June 29, 2016: https://webprod5.hc-sc.gc.ca/dpd-bdpp/start-debuter.do?lang=eng
/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Beagle dogs (3 males and 3 females per dose group) were given loperamide in gelatin capsules at 5.0, 1.25 and 0.31 mg/kg six days a week for 12 months. Some depression was seen during the first week of drug administration at 1.25 and 5 mg/kg. Behavior and appearance were normal during the rest of the experiment, except that hemorrhagic stools were seen from time to time at 5 mg/kg and soft stools at 0.31 and 1.25 mg/kg, especially during the first 6 weeks of drug administration. Blood pressure, heart rate, electrocardiogram, hemograms, serum analysis and urinalysis were normal throughout the experiment. Gross pathologic and histologic examinations failed to reveal any dose or drug-related changes.
Health Canada; Product Monograph for Imodium Caplets, Imodium Quick-Dissolve,Imodium Calming Liquid and Imodium Liqui-Gels (Loperamide Hydrochloride), Drug Identification Number (DIN): 02230542 p.24 (Date of Revision: November 10, 2011). Available from, as of June 29, 2016: https://webprod5.hc-sc.gc.ca/dpd-bdpp/start-debuter.do?lang=eng
/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ In a study in rats using loperamide dosages up to 133 times the maximum human dosage (on a mg/kg basis) for 18 months, there was no evidence of carcinogenicity.
American Society of Health-System Pharmacists 2016; Drug Information 2016. Bethesda, MD. 2016, p. 2971
For more Non-Human Toxicity Excerpts (Complete) data for Loperamide (17 total), please visit the HSDB record page.

12.1.11 Non-Human Toxicity Values

LD50 Dog iv 2.8 mg/kg
Health Canada; Product Monograph for Imodium Caplets, Imodium Quick-Dissolve,Imodium Calming Liquid and Imodium Liqui-Gels (Loperamide Hydrochloride), Drug Identification Number (DIN): 02230542 p.23 (Date of Revision: November 10, 2011). Available from, as of June 29, 2016: https://webprod5.hc-sc.gc.ca/dpd-bdpp/start-debuter.do?lang=eng
LD50 Dog oral >40 mg/kg
Health Canada; Product Monograph for Imodium Caplets, Imodium Quick-Dissolve,Imodium Calming Liquid and Imodium Liqui-Gels (Loperamide Hydrochloride), Drug Identification Number (DIN): 02230542 p.23 (Date of Revision: November 10, 2011). Available from, as of June 29, 2016: https://webprod5.hc-sc.gc.ca/dpd-bdpp/start-debuter.do?lang=eng
LD50 Guinea pig oral 41.5 mg/kg
Health Canada; Product Monograph for Imodium Caplets, Imodium Quick-Dissolve,Imodium Calming Liquid and Imodium Liqui-Gels (Loperamide Hydrochloride), Drug Identification Number (DIN): 02230542 p.23 (Date of Revision: November 10, 2011). Available from, as of June 29, 2016: https://webprod5.hc-sc.gc.ca/dpd-bdpp/start-debuter.do?lang=eng
LD50 Rat (young, female) oral 261 mg/kg
Health Canada; Product Monograph for Imodium Caplets, Imodium Quick-Dissolve,Imodium Calming Liquid and Imodium Liqui-Gels (Loperamide Hydrochloride), Drug Identification Number (DIN): 02230542 p.23 (Date of Revision: November 10, 2011). Available from, as of June 29, 2016: https://webprod5.hc-sc.gc.ca/dpd-bdpp/start-debuter.do?lang=eng
For more Non-Human Toxicity Values (Complete) data for Loperamide (10 total), please visit the HSDB record page.

12.1.12 Ongoing Test Status

EPA has released the Interactive Chemical Safety for Sustainability (iCSS) Dashboard. The iCSS Dashboard provides an interactive tool to explore rapid, automated (or in vitro high-throughput) chemical screening data generated by the Toxicity Forecaster (ToxCast) project and the federal Toxicity Testing in the 21st century (Tox21) collaboration. /The title compound was tested by ToxCast and/or Tox21 assays/[USEPA; ICSS Dashboard Application; Available from, as of July 7, 2016: http://actor.epa.gov/dashboard/]

12.1.13 Populations at Special Risk

Safety and efficacy of loperamide in children younger than 2 years of age have not been established. Loperamide should be used with particular caution in young children because of the greater variability of response in this age group. The presence of dehydration, especially in younger children, may further influence the variability of response to the drug.
American Society of Health-System Pharmacists 2016; Drug Information 2016. Bethesda, MD. 2016, p. 2971
Patients with hepatic dysfunction should be monitored for signs of CNS toxicity due to the extensive first pass metabolism of loperamide in the liver. Although no pharmacokinetic data are available in patients with hepatic impairment, loperamide HCl should be used with caution in such patients because of reduced first pass metabolism. This medicine must be used with caution in patients with hepatic impairment as it may result in a relative overdose leading to CNS toxicity.
Health Canada; Product Monograph for Imodium Caplets, Imodium Quick-Dissolve,Imodium Calming Liquid and Imodium Liqui-Gels (Loperamide Hydrochloride), Drug Identification Number (DIN): 02230542 p.5 (Date of Revision: November 10, 2011). Available from, as of June 29, 2016: https://webprod5.hc-sc.gc.ca/dpd-bdpp/start-debuter.do?lang=eng

12.1.14 Protein Binding

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

12.2 Ecological Information

12.2.1 Environmental Fate / Exposure Summary

Loperamide's production and administration as a medication and drug of abuse may result in its release to the environment through various waste streams. If released to air, an estimated vapor pressure of 7.9X10-16 mm Hg at 25 °C indicates loperamide will exist solely in the particulate phase in the atmosphere. Particulate-phase loperamide will be removed from the atmosphere by wet and dry deposition. Loperamide does not contain chromophores that absorb at wavelengths >290 nm and, therefore, is not expected to be susceptible to direct photolysis by sunlight. If released to soil, loperamide is expected to be immobile based upon an estimated Koc of 5.2X10+5. The pKa of loperamide is 9.41, indicating that this compound will exist almost entirely in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts. Volatilization from moist soil is not expected because the compound exists as a cation and cations do not volatilize. Loperamide is not expected to volatilize from dry soil surfaces based upon its vapor pressure. Loperamide is predicted to be not readily biodegradable n soil and water. If released into water, loperamide is expected to adsorb to suspended solids and sediment based upon the estimated Koc. The pKa indicates loperamide will exist almost entirely in the cation form at pH values of 5 to 9 and, therefore, volatilization from water surfaces is not expected to be an important fate process. An estimated BCF of 1200 suggests the potential for bioconcentration in aquatic organisms is very high, assuming the compound is not metabolized by the organism. Hydrolysis is not expected to be an important environmental fate process since this compound lacks functional groups that hydrolyze under environmental conditions (pH 5 to 9). Occupational exposure to loperamide may occur through inhalation and dermal contact with this compound at workplaces where loperamide is produced or used. Limited monitoring data indicate that the general population may be exposed to loperamide via ingestion of drinking water. The general public is likely to be exposed to loperamide when ingesting over-the-counter medications containing loperamide. (SRC)

12.2.2 Artificial Pollution Sources

Loperamide's production and administration as a medication(1) and drug of abuse(2) may result in its release to the environment through various waste streams(SRC). It's potential use as a marine anti-fouling agent(3) will result in its direct release to the environment(SRC).
(1) O'Neil MJ, ed; The Merck Index. 15 th ed., Cambridge, UK: Royal Society of Chemistry, p. 1035 (2013)
(2) FDA; FDA Drug Safety Communication. 6-07-2016. Available from, as of July 13, 2016: https://www.fda.gov/Drugs/DrugSafety/ucm504617.htm
(3) Cyu YT et al; Int J Mol Sci 15: 9255-84 (2014). Available from, as of Jul 6, 2016: https://www.mdpi.com/1422-0067/15/6/9255/htm

12.2.3 Environmental Fate

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 5.2X10+5(SRC), determined from a structure estimation method(2), indicates that loperamide is expected to be immobile in soil(SRC). The pKa of loperamide is 9.41(3), indicating that this compound will exist almost entirely in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). Volatilization from moist soil is not expected because the compound exists as a cation and cations do not volatilize. Loperamide is predicted to be not readily biodegradable(5).
(1) Swann RL et al; Res Rev 85: 17-28 (1983)
(2) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.1. Nov, 2012. Available from, as of July 6, 2016: https://www2.epa.gov/tsca-screening-tools
(3) DrugBank; Loperamide. Canadian Inst Health. Available from, as of July 7, 2016: https://www.drugbank.ca/salts/DBSALT000709
(4) Doucette WJ; pp. 141-188 in Handbook of Property Estimation Methods for Chemicals. Boethling RS, Mackay D, eds. Boca Raton, FL: Lewis Publ (2000)
(5) Cyu YT et al; Int J Mol Sci 15: 9255-84 (2014). Available from, as of Jul 6, 2016: https://www.mdpi.com/1422-0067/15/6/9255/htm
AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 5.2X10+5(SRC), determined from a structure estimation method(2), indicates that loperamide is expected to adsorb to suspended solids and sediment(SRC). A pKa of 9.41(3) indicates loperamide will exist almost entirely in the cation form at pH values of 5 to 9 and, therefore, volatilization from water or moist soil surfaces is not expected to be an important fate process. According to a classification scheme(4), an estimated BCF of 1200, provided the compound is not metabolized by the organism(SRC), from an estimated log Kow of 5.15(2) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is very high(SRC). Loperamide is predicted to be not readily biodegradable(5).
(1) Swann RL et al; Res Rev 85: 17-28 (1983)
(2) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.1. Nov, 2012. Available from, as of July 6, 2016: https://www2.epa.gov/tsca-screening-tools
(3) DrugBank; Loperamide. Canadian Inst Health. Available from, as of July 7, 2016: https://www.drugbank.ca/salts/DBSALT000709
(4) Franke C et al; Chemosphere 29: 1501-14 (1994)
(5) Cyu YT et al; Int J Mol Sci 15: 9255-84 (2014). Available from, as of Jul 6, 2016: https://www.mdpi.com/1422-0067/15/6/9255/htm
ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), loperamide, which has an estimated vapor pressure of 7.9X10-16 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase loperamide may be removed from the air by wet and dry deposition(SRC). Loperamide does not contain chromophores that absorb at wavelengths >290 nm(3) and, therefore, is not expected to be susceptible to direct photolysis by sunlight(SRC).
(1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988)
(2) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.1. Nov, 2012. Available from, as of Jul 6, 2016: https://www2.epa.gov/tsca-screening-tools
(3) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993)
(4) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 8-12 (1990)

12.2.4 Environmental Biodegradation

AEROBIC: Loperamide is predicted to be not readily biodegradable(1).
(1) Cyu YT et al; Int J Mol Sci 15: 9255-84 (2014). Available from, as of Jul 6, 2016: https://www.mdpi.com/1422-0067/15/6/9255/htm

12.2.5 Environmental Abiotic Degradation

Loperamide is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(1). Loperamide does not contain chromophores that absorb at wavelengths >290 nm(1) and, therefore, is not expected to be susceptible to direct photolysis by sunlight(SRC).
(1) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 7-4, 7-5, 8-12 (1990)

12.2.6 Environmental Bioconcentration

An estimated BCF of 1200 was calculated in fish for loperamide(SRC), using an estimated log Kow of 5.15(1) and a regression-derived equation(1). According to a classification scheme(2), this BCF suggests the potential for bioconcentration in aquatic organisms is very high(SRC), provided the compound is not metabolized by the organism(SRC).
(1) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.1. Nov, 2012. Available from, as of July 6, 2016: https://www2.epa.gov/tsca-screening-tools
(2) Franke C et al; Chemosphere 29: 1501-14 (1994)

12.2.7 Soil Adsorption / Mobility

Using a structure estimation method based on molecular connectivity indices(1), the Koc of loperamide can be estimated to be 5.2X10+5(SRC). According to a classification scheme(2), this estimated Koc value suggests that loperamide is expected to be immobile in soil. The pKa of loperamide is 9.41(3), indicating that this compound will exist almost entirely in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4).
(1) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.1. Nov, 2012. Available from, as of July 6, 2016: https://www2.epa.gov/tsca-screening-tools
(2) Swann RL et al; Res Rev 85: 17-28 (1983)
(3) DrugBank; Loperamide. Canadian Inst Health. Available from, as of July 7, 2016: https://www.drugbank.ca/salts/DBSALT000709
(4) Doucette WJ; pp. 141-188 in Handbook of Property Estimation Methods for Chemicals. Boethling RS, Mackay D, eds. Boca Raton, FL: Lewis Publ (2000)

12.2.8 Volatilization from Water / Soil

A pKa of 9.41(1) indicates loperamide will exist almost entirely in the cation form at pH values of 5 to 9 and, therefore, volatilization from water or moist soil surfaces is not expected to be an important fate process. Loperamide is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 7.9X10-16 mm Hg(SRC), determined from a fragment constant method(2).
(1) DrugBank; Loperamide. Canadian Inst Health. Available from, as of July 7, 2016: https://www.drugbank.ca/salts/DBSALT000709
(2) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.1. Nov, 2012. Available from, as of Jul 6, 2016: https://www2.epa.gov/tsca-screening-tools

12.2.9 Environmental Water Concentrations

DRINKING WATER: Loperamide was detected at <11.5 ng/L in well water samples from the Borrego Valley, CA northwest of San Diego, sampled on July 17,2013(1).
(1) USGS; California Water Data. USGS Data Mapper. Survey Site Number 331211116185101; state well number 011S006E23J001S. Available from, as of July 6, 2016: https://ca.water.usgs.gov/projects/borrego/data/Pharmaceuticals_table_20151119.xlsx
SURFACE WATER: Loperamide has been reported in the environment(1). It has been detected in unspecified surface water; detection limit = 0.51 ng/L(2).
(1) Roig B, D'Aco V; pp 34-62 in Pharmaceuticals in the Environment. Iss Environ Sci Technol No. 41. Hester RE, Harrison RM, eds. Oxford, UK: Royal Soc Chem (2016)
(2) Grabic R et al; Talanta 100: 183-195 (2012). Available from, as of Jul 6, 2016: https://www.sciencedirect.com/science/article/pii/S0039914012007370

12.2.10 Probable Routes of Human Exposure

Occupational exposure to loperamide may occur through inhalation and dermal contact with this compound at workplaces where loperamide is produced or used. Limited monitoring data indicate that the general population may be exposed to loperamide via ingestion of drinking water. The general public is likely to be exposed to loperamide when ingesting over-the-counter medications containing loperamide. (SRC)

13 Associated Disorders and Diseases

14 Literature

14.1 Consolidated References

14.2 NLM Curated PubMed Citations

14.3 Springer Nature References

14.4 Thieme References

14.5 Nature Journal References

14.6 Chemical Co-Occurrences in Literature

14.7 Chemical-Gene Co-Occurrences in Literature

14.8 Chemical-Disease Co-Occurrences in Literature

15 Patents

15.1 Depositor-Supplied Patent Identifiers

15.2 WIPO PATENTSCOPE

15.3 Chemical Co-Occurrences in Patents

15.4 Chemical-Disease Co-Occurrences in Patents

15.5 Chemical-Gene Co-Occurrences in Patents

16 Interactions and Pathways

16.1 Chemical-Target Interactions

16.2 Drug-Drug Interactions

16.3 Pathways

17 Biological Test Results

17.1 BioAssay Results

18 Taxonomy

19 Classification

19.1 MeSH Tree

19.2 NCI Thesaurus Tree

19.3 ChEBI Ontology

19.4 KEGG: ATC

19.5 KEGG: Target-based Classification of Drugs

19.6 KEGG: Risk Category of Japanese OTC Drugs

19.7 KEGG: Drug Groups

19.8 WHO ATC Classification System

19.9 FDA Pharm Classes

19.10 ChemIDplus

19.11 IUPHAR / BPS Guide to PHARMACOLOGY Target Classification

19.12 ChEMBL Target Tree

19.13 UN GHS Classification

19.14 NORMAN Suspect List Exchange Classification

19.15 CCSBase Classification

19.16 EPA DSSTox Classification

19.17 MolGenie Organic Chemistry Ontology

20 Information Sources

  1. Australian Industrial Chemicals Introduction Scheme (AICIS)
    1-Piperidinebutanamide, 4-(4-chlorophenyl)-4-hydroxy-N,N-dimethyl-.alpha.,.alpha.-diphenyl-
    https://services.industrialchemicals.gov.au/search-assessments/
  2. CAS Common Chemistry
    LICENSE
    The data from CAS Common Chemistry is provided under a CC-BY-NC 4.0 license, unless otherwise stated.
    https://creativecommons.org/licenses/by-nc/4.0/
  3. ChemIDplus
    ChemIDplus Chemical Information Classification
    https://pubchem.ncbi.nlm.nih.gov/source/ChemIDplus
  4. DrugBank
    LICENSE
    Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode)
    https://www.drugbank.ca/legal/terms_of_use
  5. EPA DSSTox
    CompTox Chemicals Dashboard Chemical Lists
    https://comptox.epa.gov/dashboard/chemical-lists/
  6. European Chemicals Agency (ECHA)
    LICENSE
    Use of the information, documents and data from the ECHA website is subject to the terms and conditions of this Legal Notice, and subject to other binding limitations provided for under applicable law, the information, documents and data made available on the ECHA website may be reproduced, distributed and/or used, totally or in part, for non-commercial purposes provided that ECHA is acknowledged as the source: "Source: European Chemicals Agency, http://echa.europa.eu/". Such acknowledgement must be included in each copy of the material. ECHA permits and encourages organisations and individuals to create links to the ECHA website under the following cumulative conditions: Links can only be made to webpages that provide a link to the Legal Notice page.
    https://echa.europa.eu/web/guest/legal-notice
  7. FDA Global Substance Registration System (GSRS)
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  8. Hazardous Substances Data Bank (HSDB)
  9. Human Metabolome Database (HMDB)
    LICENSE
    HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications.
    http://www.hmdb.ca/citing
  10. BindingDB
    LICENSE
    All data curated by BindingDB staff are provided under the Creative Commons Attribution 3.0 License (https://creativecommons.org/licenses/by/3.0/us/).
    https://www.bindingdb.org/rwd/bind/info.jsp
    4-(4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl)-N,N-dimethyl-2,2-diphenylbutanamide
    https://www.bindingdb.org/rwd/bind/chemsearch/marvin/MolStructure.jsp?monomerid=50017698
  11. Drug Gene Interaction database (DGIdb)
    LICENSE
    The data used in DGIdb is all open access and where possible made available as raw data dumps in the downloads section.
    http://www.dgidb.org/downloads
  12. IUPHAR/BPS Guide to PHARMACOLOGY
    LICENSE
    The Guide to PHARMACOLOGY database is licensed under the Open Data Commons Open Database License (ODbL) https://opendatacommons.org/licenses/odbl/. Its contents are licensed under a Creative Commons Attribution-ShareAlike 4.0 International License (http://creativecommons.org/licenses/by-sa/4.0/)
    https://www.guidetopharmacology.org/about.jsp#license
    Guide to Pharmacology Target Classification
    https://www.guidetopharmacology.org/targets.jsp
  13. Therapeutic Target Database (TTD)
  14. CCSbase
    CCSbase Classification
    https://ccsbase.net/
  15. ChEBI
  16. FDA Pharm Classes
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  17. LiverTox
  18. NCI Thesaurus (NCIt)
    LICENSE
    Unless otherwise indicated, all text within NCI products is free of copyright and may be reused without our permission. Credit the National Cancer Institute as the source.
    https://www.cancer.gov/policies/copyright-reuse
  19. Open Targets
    LICENSE
    Datasets generated by the Open Targets Platform are freely available for download.
    https://platform-docs.opentargets.org/licence
  20. ChEMBL
    LICENSE
    Access to the web interface of ChEMBL is made under the EBI's Terms of Use (http://www.ebi.ac.uk/Information/termsofuse.html). The ChEMBL data is made available on a Creative Commons Attribution-Share Alike 3.0 Unported License (http://creativecommons.org/licenses/by-sa/3.0/).
    http://www.ebi.ac.uk/Information/termsofuse.html
  21. ClinicalTrials.gov
    LICENSE
    The ClinicalTrials.gov data carry an international copyright outside the United States and its Territories or Possessions. Some ClinicalTrials.gov data may be subject to the copyright of third parties; you should consult these entities for any additional terms of use.
    https://clinicaltrials.gov/ct2/about-site/terms-conditions#Use
  22. Crystallography Open Database (COD)
    LICENSE
    All data in the COD and the database itself are dedicated to the public domain and licensed under the CC0 License. Users of the data should acknowledge the original authors of the structural data.
    https://creativecommons.org/publicdomain/zero/1.0/
  23. Drug Induced Liver Injury Rank (DILIrank) Dataset
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  24. NORMAN Suspect List Exchange
    LICENSE
    Data: CC-BY 4.0; Code (hosted by ECI, LCSB): Artistic-2.0
    https://creativecommons.org/licenses/by/4.0/
    LOPERAMIDE
    NORMAN Suspect List Exchange Classification
    https://www.norman-network.com/nds/SLE/
  25. Drugs and Lactation Database (LactMed)
  26. WHO Model Lists of Essential Medicines
    LICENSE
    Permission from WHO is not required for the use of WHO materials issued under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Intergovernmental Organization (CC BY-NC-SA 3.0 IGO) license.
    https://www.who.int/about/policies/publishing/copyright
  27. EU Clinical Trials Register
  28. NIST Mass Spectrometry Data Center
    LICENSE
    Data covered by the Standard Reference Data Act of 1968 as amended.
    https://www.nist.gov/srd/public-law
  29. Japan Chemical Substance Dictionary (Nikkaji)
  30. KEGG
    LICENSE
    Academic users may freely use the KEGG website. Non-academic use of KEGG generally requires a commercial license
    https://www.kegg.jp/kegg/legal.html
    Anatomical Therapeutic Chemical (ATC) classification
    http://www.genome.jp/kegg-bin/get_htext?br08303.keg
    Target-based classification of drugs
    http://www.genome.jp/kegg-bin/get_htext?br08310.keg
    Risk category of Japanese OTC drugs
    http://www.genome.jp/kegg-bin/get_htext?br08312.keg
  31. Kruve Lab, Ionization & Mass Spectrometry, Stockholm University
    loperamide
  32. MassBank Europe
  33. MassBank of North America (MoNA)
    LICENSE
    The content of the MoNA database is licensed under CC BY 4.0.
    https://mona.fiehnlab.ucdavis.edu/documentation/license
  34. Metabolomics Workbench
  35. Natural Product Activity and Species Source (NPASS)
  36. Nature Chemical Biology
  37. SpectraBase
  38. NLM RxNorm Terminology
    LICENSE
    The RxNorm Terminology is created by the National Library of Medicine (NLM) and is in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from NLM. Credit to the U.S. National Library of Medicine as the source is appreciated but not required. The full RxNorm dataset requires a free license.
    https://www.nlm.nih.gov/research/umls/rxnorm/docs/termsofservice.html
  39. WHO Anatomical Therapeutic Chemical (ATC) Classification
    LICENSE
    Use of all or parts of the material requires reference to the WHO Collaborating Centre for Drug Statistics Methodology. Copying and distribution for commercial purposes is not allowed. Changing or manipulating the material is not allowed.
    https://www.whocc.no/copyright_disclaimer/
  40. PharmGKB
    LICENSE
    PharmGKB data are subject to the Creative Commons Attribution-ShareALike 4.0 license (https://creativecommons.org/licenses/by-sa/4.0/).
    https://www.pharmgkb.org/page/policies
  41. Pharos
    LICENSE
    Data accessed from Pharos and TCRD is publicly available from the primary sources listed above. Please respect their individual licenses regarding proper use and redistribution.
    https://pharos.nih.gov/about
  42. Springer Nature
  43. Thieme Chemistry
    LICENSE
    The Thieme Chemistry contribution within PubChem is provided under a CC-BY-NC-ND 4.0 license, unless otherwise stated.
    https://creativecommons.org/licenses/by-nc-nd/4.0/
  44. USGS Health-Based Screening Levels for Evaluating Water-Quality Data
  45. Wikidata
  46. Wikipedia
  47. Medical Subject Headings (MeSH)
    LICENSE
    Works produced by the U.S. government are not subject to copyright protection in the United States. Any such works found on National Library of Medicine (NLM) Web sites may be freely used or reproduced without permission in the U.S.
    https://www.nlm.nih.gov/copyright.html
  48. PubChem
  49. GHS Classification (UNECE)
  50. MolGenie
    MolGenie Organic Chemistry Ontology
    https://github.com/MolGenie/ontology/
  51. PATENTSCOPE (WIPO)
  52. NCBI
CONTENTS