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Identification
NameLoperamide
Accession NumberDB00836  (APRD00275)
Typesmall molecule
Groupsapproved
Description

One of the long-acting synthetic antidiarrheals; it is not significantly absorbed from the gut, and has no effect on the adrenergic system or central nervous system, but may antagonize histamine and interfere with acetylcholine release locally. [PubChem]

Structure
Thumb
Synonyms
SynonymLanguageCode
LoperamidGermanINN
LoperamidaSpanishINN
LopéramideFrenchINN
LoperamidumLatinINN
Salts
Name/CAS Structure Properties
Loperamide hydrochloride
Thumb
  • InChI Key: PGYPOBZJRVSMDS-UHFFFAOYSA-N
  • Monoisotopic Mass: 512.199733756
  • Average Mass: 513.498
DBSALT000709
Brand names
NameCompany
DimorNordic Drugs
FortasecEsteve
ImodiumJohnson & Johnson
Imodium A-DJohnson & Johnson
Kaopectate IIChattem, Inc.
LopediumSandoz
Lopedium expressSandoz
LoperacapValeant
LopexOrion
Maalox Anti-DiarrhealNovartis International AG
Pepto Diarrhea ControlProcter & Gamble
Brand mixtures
Brand NameIngredients
Imodium PlusLoperamide and Simeticone
Categories
CAS number53179-11-6
WeightAverage: 477.038
Monoisotopic: 476.223056017
Chemical FormulaC29H33ClN2O2
InChI KeyRDOIQAHITMMDAJ-UHFFFAOYSA-N
InChI
InChI=1S/C29H33ClN2O2/c1-31(2)27(33)29(24-9-5-3-6-10-24,25-11-7-4-8-12-25)19-22-32-20-17-28(34,18-21-32)23-13-15-26(30)16-14-23/h3-16,34H,17-22H2,1-2H3
IUPAC Name
4-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-N,N-dimethyl-2,2-diphenylbutanamide
SMILES
CN(C)C(=O)C(CCN1CCC(O)(CC1)C1=CC=C(Cl)C=C1)(C1=CC=CC=C1)C1=CC=CC=C1
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassBenzenoids
ClassBenzene and Substituted Derivatives
SubclassDiphenylmethanes
Direct parentDiphenylmethanes
Alternative parentsPhenylpiperidines; Phenylpropylamines; Chlorobenzenes; Aryl Chlorides; Tertiary Alcohols; Tertiary Carboxylic Acid Amides; Tertiary Amines; Enolates; Polyamines; Carboxylic Acids; Organochlorides
Substituentsphenylpropylamine; chlorobenzene; aryl chloride; piperidine; aryl halide; tertiary alcohol; tertiary carboxylic acid amide; carboxamide group; tertiary amine; polyamine; enolate; carboxylic acid derivative; carboxylic acid; amine; organohalogen; organochloride; alcohol; organonitrogen compound
Classification descriptionThis compound belongs to the diphenylmethanes. These are compounds containing a diphenylmethane moiety, which consists of a methane wherein two hydrogen atoms are replaced by two phenyl groups.
Pharmacology
IndicationFor the control and symptomatic relief of acute nonspecific diarrhea and of chronic diarrhea associated with inflammatory bowel disease or gastroenteritis. Also used for reducing the volume of discharge from ileostomies.
PharmacodynamicsLoperamide is a synthetic anti-diarrheal indicated for the control and symptomatic relief of acute nonspecific diarrhea and of chronic diarrhea associated with inflammatory bowel disease. Loperamide is also indicated for reducing the volume of discharge from ileostomies. In man, Loperamide prolongs the transit time of the intestinal contents. It reduces the daily fecal volume, increases the viscosity and bulk density, and diminishes the loss of fluid and electrolytes. Tolerance to the antidiarrheal effect has not been observed. Loperamide is an opioid receptor agonist and acts on the mu opioid receptors in the myenteric plexus large intestines; it does not affect the central nervous system like other opioids. It works specifically by decreasing the activity of the myenteric plexus which decreases the motility of the circular and longitudinal smooth muscles of the intestinal wall. This increases the amount of time substances stay in the intestine, allowing for more water to be absorbed out of the fecal matter. Loperamide also decreases colonic mass movements and suppresses the gastrocolic reflex.
Mechanism of actionIn vitro and animal studies show that Loperamide acts by slowing intestinal motility and by affecting water and electrolyte movement through the bowel. Loperamide inhibits peristaltic activity by a direct effect on the circular and longitudinal muscles of the intestinal wall. It is a non-selective calcium channel blocker and binds to opioid mu-receptors. Evidence also suggests that at higher concentrations it binds to calmodulin.
AbsorptionNot significantly absorbed from the gut
Volume of distributionNot Available
Protein binding97%
Metabolism

Hepatic

Route of eliminationExcretion of the unchanged loperamide and its metabolites mainly occurs through the feces.
Half life9.1 to 14.4 hours (average 10.8 hours)
ClearanceNot Available
ToxicityOral, mouse: LD50 = 105 mg/kg. Symptoms of overdose include constipation, drowsiness, lethargy, and nausea.
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 0.9878
Blood Brain Barrier + 0.7709
Caco-2 permeable + 0.5875
P-glycoprotein substrate Substrate 0.7476
P-glycoprotein inhibitor I Inhibitor 0.8277
P-glycoprotein inhibitor II Inhibitor 0.8387
Renal organic cation transporter Inhibitor 0.5059
CYP450 2C9 substrate Non-substrate 0.8057
CYP450 2D6 substrate Non-substrate 0.5315
CYP450 3A4 substrate Substrate 0.7918
CYP450 1A2 substrate Non-inhibitor 0.9045
CYP450 2C9 substrate Non-inhibitor 0.9154
CYP450 2D6 substrate Inhibitor 0.8933
CYP450 2C19 substrate Non-inhibitor 0.9026
CYP450 3A4 substrate Non-inhibitor 0.8309
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.9207
Ames test Non AMES toxic 0.768
Carcinogenicity Non-carcinogens 0.8564
Biodegradation Not ready biodegradable 0.9953
Rat acute toxicity 3.6560 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9461
hERG inhibition (predictor II) Inhibitor 0.7639
Pharmacoeconomics
Manufacturers
  • Mcneil consumer healthcare
  • Mcneil pediatrics
  • Janssen pharmaceutica products lp
Packagers
Dosage forms
FormRouteStrength
SolutionOral
TabletOral
Prices
Unit descriptionCostUnit
Loperamide hcl powder26.01USDg
Loperamide HCl 2 mg capsule0.64USDcapsule
Imodium a-d 2 mg caplet0.49USDcaplet
Imodium advanced caplet0.46USDcaplet
Imodium ms relief caplet0.46USDcaplet
Kaopectate 262 mg caplet0.37USDcaplet
Loperamide 2 mg caplet0.37USDcaplet
Qc anti-diarrheal adv caplet0.3USDcaplet
Diamode 2 mg tablet0.28USDtablet
Kaopectate 240 mg softgel0.25USDsoftgel capsule
Anti-diarrheal 2 mg caplet0.18USDcaplet
CVS Pharmacy anti-diarrheal 2 mg caplet0.14USDcaplet
Kaopectate children's suspension0.02USDml
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
CountryPatent NumberApprovedExpires (estimated)
Canada21346112002-12-242014-10-28
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point222.1U.S. Patent 3,714,159; 3,884,916.
water solubilitySlightNot Available
logP5.5Not Available
Predicted Properties
PropertyValueSource
water solubility8.60e-04 g/lALOGPS
logP4.44ALOGPS
logP4.77ChemAxon
logS-5.7ALOGPS
pKa (strongest acidic)13.96ChemAxon
pKa (strongest basic)9.41ChemAxon
physiological charge1ChemAxon
hydrogen acceptor count3ChemAxon
hydrogen donor count1ChemAxon
polar surface area43.78ChemAxon
rotatable bond count7ChemAxon
refractivity139.32ChemAxon
polarizability52.67ChemAxon
number of rings4ChemAxon
bioavailability1ChemAxon
rule of fiveYesChemAxon
Ghose filterNoChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleYesChemAxon
Spectra
SpectraMS/MSLC-MS1D NMR2D NMR
References
Synthesis Reference

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

US20110159058
General ReferenceNot Available
External Links
ResourceLink
KEGG DrugD08144
KEGG CompoundC07080
PubChem Compound3955
PubChem Substance46504591
ChemSpider3818
BindingDB50017698
ChEBI6532
ChEMBLCHEMBL841
Therapeutic Targets DatabaseDAP000425
PharmGKBPA450262
Drug Product Database2240415
RxListhttp://www.rxlist.com/cgi/generic3/loperamide.htm
Drugs.comhttp://www.drugs.com/cdi/loperamide.html
PDRhealthhttp://www.pdrhealth.com/drug_info/rxdrugprofiles/drugs/imo1206.shtml
WikipediaLoperamide
ATC CodesA07DA03A07DA05
AHFS Codes
  • 56:08.00
PDB EntriesNot Available
FDA labelshow(55.5 KB)
MSDSshow(73.8 KB)
Interactions
Drug InteractionsNot Available
Food InteractionsNot Available

Targets

1. Mu-type opioid receptor

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: agonist

Components

Name UniProt ID Details
Mu-type opioid receptor P35372 Details

References:

  1. DeHaven-Hudkins DL, Burgos LC, Cassel JA, Daubert JD, DeHaven RN, Mansson E, Nagasaka H, Yu G, Yaksh T: Loperamide (ADL 2-1294), an opioid antihyperalgesic agent with peripheral selectivity. J Pharmacol Exp Ther. 1999 Apr;289(1):494-502. Pubmed
  2. Tan-No K, Niijima F, Nakagawasai O, Sato T, Satoh S, Tadano T: Development of tolerance to the inhibitory effect of loperamide on gastrointestinal transit in mice. Eur J Pharm Sci. 2003 Nov;20(3):357-63. Pubmed
  3. Roge J, Baumer P, Berard H, Schwartz JC, Lecomte JM: The enkephalinase inhibitor, acetorphan, in acute diarrhoea. A double-blind, controlled clinical trial versus loperamide. Scand J Gastroenterol. 1993 Apr;28(4):352-4. Pubmed
  4. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  5. Giagnoni G, Casiraghi L, Senini R, Revel L, Parolaro D, Sala M, Gori E: Loperamide: evidence of interaction with mu and delta opioid receptors. Life Sci. 1983;33 Suppl 1:315-8. Pubmed
  6. di Bosco AM, Grieco P, Diurno MV, Campiglia P, Novellino E, Mazzoni O: Binding site of loperamide: automated docking of loperamide in human mu- and delta-opioid receptors. Chem Biol Drug Des. 2008 Apr;71(4):328-35. Epub 2008 Feb 12. Pubmed

2. Delta-type opioid receptor

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: agonist

Components

Name UniProt ID Details
Delta-type opioid receptor P41143 Details

References:

  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  2. Giagnoni G, Casiraghi L, Senini R, Revel L, Parolaro D, Sala M, Gori E: Loperamide: evidence of interaction with mu and delta opioid receptors. Life Sci. 1983;33 Suppl 1:315-8. Pubmed
  3. di Bosco AM, Grieco P, Diurno MV, Campiglia P, Novellino E, Mazzoni O: Binding site of loperamide: automated docking of loperamide in human mu- and delta-opioid receptors. Chem Biol Drug Des. 2008 Apr;71(4):328-35. Epub 2008 Feb 12. Pubmed

3. Kappa-type opioid receptor

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: agonist

Components

Name UniProt ID Details
Kappa-type opioid receptor P41145 Details

References:

  1. DeHaven-Hudkins DL, Burgos LC, Cassel JA, Daubert JD, DeHaven RN, Mansson E, Nagasaka H, Yu G, Yaksh T: Loperamide (ADL 2-1294), an opioid antihyperalgesic agent with peripheral selectivity. J Pharmacol Exp Ther. 1999 Apr;289(1):494-502. Pubmed

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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Voltage-dependent P/Q-type calcium channel subunit alpha-1A O00555 Details

References:

  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed
  3. Church J, Fletcher EJ, Abdel-Hamid K, MacDonald JF: Loperamide blocks high-voltage-activated calcium channels and N-methyl-D-aspartate-evoked responses in rat and mouse cultured hippocampal pyramidal neurons. Mol Pharmacol. 1994 Apr;45(4):747-57. Pubmed

5. Pro-opiomelanocortin

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: modulator

Components

Name UniProt ID Details
Pro-opiomelanocortin P01189 Details

References:

  1. Nomura A, Iwasaki Y, Aoki Y, Yamamori E, Mutsuga N, Yoshida M, Asai M, Oiso Y, Saito H: Effects of loperamide and other opioid-related substances on the transcriptional regulation of the rat pro-opiomelanocortin gene in AtT20 cells. Neuroendocrinology. 2001 Aug;74(2):87-94. Pubmed
  2. Auernhammer CJ, Stalla GK, Lange M, Pfeiffer A, Muller OA: Effects of loperamide on the human hypothalamo-pituitary-adrenal axis in vivo and in vitro. J Clin Endocrinol Metab. 1992 Aug;75(2):552-7. Pubmed
  3. Ambrosi B, Bochicchio D, Ferrario R, Colombo P, Faglia G: Effects of the opiate agonist loperamide on pituitary-adrenal function in patients with suspected hypercortisolism. J Endocrinol Invest. 1989 Jan;12(1):31-5. Pubmed
  4. Ambrosi B, Bochicchio D, Colombo P, Ferrario R, Faglia G: Loperamide modifies but does not block the corticotropin-releasing hormone-induced ACTH response in patients with Addison’s disease. Horm Metab Res Suppl. 1987;16:74-5. Pubmed
  5. Bochicchio D, Ambrosi B, Faglia G: Loperamide, an opiate analog, differently modifies the adrenocorticotropin responses to corticotropin-releasing hormone and lysine vasopressin in patients with Addison’s disease. Neuroendocrinology. 1988 Dec;48(6):611-4. Pubmed

6. Calmodulin

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Calmodulin P62158 Details

References:

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

Enzymes

1. Cytochrome P450 3A4

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 3A4 P08684 Details

References:

  1. Baker DE: Loperamide: a pharmacological review. Rev Gastroenterol Disord. 2007;7 Suppl 3:S11-8. Pubmed
  2. Kim KA, Chung J, Jung DH, Park JY: Identification of cytochrome P450 isoforms involved in the metabolism of loperamide in human liver microsomes. Eur J Clin Pharmacol. 2004 Oct;60(8):575-81. Epub 2004 Sep 8. Pubmed

2. Cytochrome P450 2C8

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 2C8 P10632 Details

References:

  1. Kim KA, Chung J, Jung DH, Park JY: Identification of cytochrome P450 isoforms involved in the metabolism of loperamide in human liver microsomes. Eur J Clin Pharmacol. 2004 Oct;60(8):575-81. Epub 2004 Sep 8. Pubmed

3. Cytochrome P450 2B6

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 2B6 P20813 Details

References:

  1. Kim KA, Chung J, Jung DH, Park JY: Identification of cytochrome P450 isoforms involved in the metabolism of loperamide in human liver microsomes. Eur J Clin Pharmacol. 2004 Oct;60(8):575-81. Epub 2004 Sep 8. Pubmed

4. Cytochrome P450 2D6

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 2D6 P10635 Details

References:

  1. Kim KA, Chung J, Jung DH, Park JY: Identification of cytochrome P450 isoforms involved in the metabolism of loperamide in human liver microsomes. Eur J Clin Pharmacol. 2004 Oct;60(8):575-81. Epub 2004 Sep 8. Pubmed

Transporters

1. Multidrug resistance protein 1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate inhibitor

Components

Name UniProt ID Details
Multidrug resistance protein 1 P08183 Details

References:

  1. Wandel C, Kim R, Wood M, Wood A: Interaction of morphine, fentanyl, sufentanil, alfentanil, and loperamide with the efflux drug transporter P-glycoprotein. Anesthesiology. 2002 Apr;96(4):913-20. Pubmed
  2. Adachi Y, Suzuki H, Sugiyama Y: Comparative studies on in vitro methods for evaluating in vivo function of MDR1 P-glycoprotein. Pharm Res. 2001 Dec;18(12):1660-8. Pubmed
  3. Schinkel AH, Wagenaar E, Mol CA, van Deemter L: P-glycoprotein in the blood-brain barrier of mice influences the brain penetration and pharmacological activity of many drugs. J Clin Invest. 1996 Jun 1;97(11):2517-24. Pubmed

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Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:12