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Identification
NameAlosetron
Accession NumberDB00969  (APRD00580)
TypeSmall Molecule
GroupsApproved, Withdrawn
Description

Alosetron is a 5-HT3 antagonist used only for the management of severe diarrhoea-predominant irritable bowel syndrome (IBS) in women. Alosetron has an antagonist action on the 5-HT3 receptors and thus may modulate serotonin-sensitive gastrointestinal (GI) processes. Alosetron was voluntarily withdrawn from the US market in November 2000 by the manufacturer due to numerous reports of severe adverse effects including ischemic colitis, severely obstructed or ruptured bowel, and death. In June 2002, the FDA approved a supplemental new drug application allowing the remarketing of the drug under restricted conditions of use.

Structure
Thumb
Synonyms
SynonymLanguageCode
2,3,4,5-Tetrahydro-5-methyl-2-((5-methyl-1H-imidazol-4-yl)methyl)-1H-pyrido(4,3-b)indol-1-oneNot AvailableNot Available
Salts
Name/CAS Structure Properties
Alosetron Hydrochloride
122852-69-1
Thumb
  • InChI Key: FNYQZOVOVDSGJH-UHFFFAOYSA-N
  • Monoisotopic Mass: 330.124738957
  • Average Mass: 330.812
DBSALT000247
Brand names
NameCompany
LotronexNot Available
Brand mixturesNot Available
CategoriesNot Available
CAS number122852-42-0
WeightAverage: 294.351
Monoisotopic: 294.148061218
Chemical FormulaC17H18N4O
InChI KeyJSWZEAMFRNKZNL-UHFFFAOYSA-N
InChI
InChI=1S/C17H18N4O/c1-11-13(19-10-18-11)9-21-8-7-15-16(17(21)22)12-5-3-4-6-14(12)20(15)2/h3-6,10H,7-9H2,1-2H3,(H,18,19)
IUPAC Name
5-methyl-2-[(5-methyl-1H-imidazol-4-yl)methyl]-1H,2H,3H,4H,5H-pyrido[4,3-b]indol-1-one
SMILES
CN1C2=C(C3=CC=CC=C13)C(=O)N(CC1=C(C)NC=N1)CC2
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassHeterocyclic Compounds
ClassIndoles and Derivatives
SubclassIndoles
Direct parentIndoles
Alternative parentsBenzene and Substituted Derivatives; N-methylpyrroles; Tertiary Carboxylic Acid Amides; Imidazoles; Tertiary Amines; Carboxylic Acids; Polyamines
Substituentsn-methylpyrrole; benzene; substituted pyrrole; n-substituted pyrrole; azole; imidazole; pyrrole; tertiary carboxylic acid amide; carboxamide group; tertiary amine; polyamine; carboxylic acid derivative; carboxylic acid; amine; organonitrogen compound
Classification descriptionThis compound belongs to the indoles. These are compounds containing an indole moiety, which consists of pyrrole ring fused to benzene to form 2,3-benzopyrrole.
Pharmacology
IndicationOnly for the treatment of symptoms of severe diarrhea-predominant irritable bowel syndrome (IBS) in women with chronic symptoms (generally lasting greater than 6 months) who does not present with anatomic or biochemical GI abnormalities and have not responded to conventional therapy.
PharmacodynamicsAlosetron is a potent and selective antagonist of the serotonin 5-HT3 receptor type. Activation of these receptors and the resulting neuronal depolarization affects the regulation of visceral pain, colonic transit, and GI secretions processes that are related to IBS. By blocking these receptors, alosetron is able to effectively control IBS.
Mechanism of actionAlosetron is a potent and selective 5-HT3 receptor antagonist. 5-HT3 receptors are nonselective cation channels that are extensively distributed on enteric neurons in the human gastrointestinal tract, as well as other peripheral and central locations. Activation of these channels and the resulting neuronal depolarization affect the regulation of visceral pain, colonic transit and gastrointestinal secretions, processes that relate to the pathophysiology of irritable bowel syndrome (IBS). 5-HT3 receptor antagonists such as alosetron inhibit activation of non-selective cation channels which results in the modulation of serotonin-sensitive GI motor and sensory processes.
Absorption50-60 %
Volume of distribution
  • 65 to 95 L
Protein binding82%
Metabolism

Hepatic, via microsomal cytochrome P450 (CYP)

Route of eliminationRenal elimination of unchanged alosetron accounts for only 6% of the dose. Alosetron is extensively metabolized in humans.
Half life1.5 hours
Clearance
  • 600 mL/min
ToxicityNot Available
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 + 0.9745
Blood Brain Barrier + 0.9139
Caco-2 permeable + 0.6511
P-glycoprotein substrate Substrate 0.8033
P-glycoprotein inhibitor I Inhibitor 0.7435
P-glycoprotein inhibitor II Non-inhibitor 0.5707
Renal organic cation transporter Inhibitor 0.7795
CYP450 2C9 substrate Non-substrate 0.7501
CYP450 2D6 substrate Non-substrate 0.9116
CYP450 3A4 substrate Substrate 0.7672
CYP450 1A2 substrate Non-inhibitor 0.5781
CYP450 2C9 substrate Non-inhibitor 0.8878
CYP450 2D6 substrate Inhibitor 0.6507
CYP450 2C19 substrate Non-inhibitor 0.9239
CYP450 3A4 substrate Non-inhibitor 0.8274
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.6424
Ames test Non AMES toxic 0.6156
Carcinogenicity Non-carcinogens 0.967
Biodegradation Not ready biodegradable 0.981
Rat acute toxicity 2.7709 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.8334
hERG inhibition (predictor II) Inhibitor 0.8554
Pharmacoeconomics
Manufacturers
  • Prometheus laboratories inc
Packagers
Dosage forms
FormRouteStrength
TabletOral
Prices
Unit descriptionCostUnit
Lotronex 1 mg tablet19.47USDtablet
Lotronex 0.5 mg tablet14.3USDtablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
CountryPatent NumberApprovedExpires (estimated)
United States53608001993-01-132013-01-13
Properties
Statesolid
Experimental Properties
PropertyValueSource
logP2Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.438ALOGPS
logP1.85ALOGPS
logP1.21ChemAxon
logS-2.8ALOGPS
pKa (Strongest Acidic)13.32ChemAxon
pKa (Strongest Basic)6.81ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area53.92 Å2ChemAxon
Rotatable Bond Count2ChemAxon
Refractivity86.41 m3·mol-1ChemAxon
Polarizability32.52 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Spectra
SpectraNot Available
References
Synthesis Reference

Buchi Reddy REGURI, Sampathkumar UPPARAPALLI, Nilam SAHU, Karunakara Rao JAVVAJI, Brahma Reddy GADE, “PROCESS FOR THE PREPARATION OF ALOSETRON.” U.S. Patent US20120178937, issued July 12, 2012.

US20120178937
General Reference
  1. Andresen V, Hollerbach S: Reassessing the benefits and risks of alosetron: what is its place in the treatment of irritable bowel syndrome? Drug Saf. 2004;27(5):283-92. Pubmed
  2. Camilleri M: Pharmacology and clinical experience with alosetron. Expert Opin Investig Drugs. 2000 Jan;9(1):147-59. Pubmed
  3. Mayer EA, Bradesi S: Alosetron and irritable bowel syndrome. Expert Opin Pharmacother. 2003 Nov;4(11):2089-98. Pubmed
  4. Rahimi R, Nikfar S, Abdollahi M: Efficacy and tolerability of alosetron for the treatment of irritable bowel syndrome in women and men: a meta-analysis of eight randomized, placebo-controlled, 12-week trials. Clin Ther. 2008 May;30(5):884-901. Pubmed
  5. Lewis JH: Alosetron for severe diarrhea-predominant irritable bowel syndrome: safety and efficacy in perspective. Expert Rev Gastroenterol Hepatol. 2010 Feb;4(1):13-29. Pubmed
External Links
ResourceLink
PubChem Compound2099
PubChem Substance46506274
ChemSpider2015
BindingDB50131429
ChEBI253342
ChEMBLCHEMBL1110
Therapeutic Targets DatabaseDAP000369
PharmGKBPA164745502
IUPHAR2296
Guide to Pharmacology2296
RxListhttp://www.rxlist.com/cgi/generic3/alosetron.htm
Drugs.comhttp://www.drugs.com/cdi/alosetron.html
WikipediaAlosetron
ATC CodesA03AE01
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelshow(208 KB)
MSDSNot Available
Interactions
Drug Interactions
Drug
ThiabendazoleThe strong CYP1A2 inhibitor, Thiabendazole, may increase the effects and toxicity of Alosetron by decreasing Alosetron metabolism and clearance. Monitor for changes in the therapeutic and adverse effects of Alosetron if Thiabendazole is initiated, discontinued or dose changed.
Food Interactions
  • Absorption is decreased by about 25% when taken with meals.
  • Take without regard to meals.

Targets

1. 5-hydroxytryptamine receptor 3A

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: antagonist

Components

Name UniProt ID Details
5-hydroxytryptamine receptor 3A P46098 Details

References:

  1. Clayton NM, Sargent R, Butler A, Gale J, Maxwell MP, Hunt AA, Barrett VJ, Cambridge D, Bountra C, Humphrey PP: The pharmacological properties of the novel selective 5-HT3 receptor antagonist, alosetron, and its effects on normal and perturbed small intestinal transit in the fasted rat. Neurogastroenterol Motil. 1999 Jun;11(3):207-17. Pubmed
  2. Mayer EA, Bradesi S: Alosetron and irritable bowel syndrome. Expert Opin Pharmacother. 2003 Nov;4(11):2089-98. Pubmed
  3. Coldwell JR, Phillis BD, Sutherland K, Howarth GS, Blackshaw LA: Increased responsiveness of rat colonic splanchnic afferents to 5-HT after inflammation and recovery. J Physiol. 2007 Feb 15;579(Pt 1):203-13. Epub 2006 Nov 30. Pubmed
  4. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  5. Houghton LA, Foster JM, Whorwell PJ: Alosetron, a 5-HT3 receptor antagonist, delays colonic transit in patients with irritable bowel syndrome and healthy volunteers. Aliment Pharmacol Ther. 2000 Jun;14(6):775-82. Pubmed
  6. Gunput MD: Review article: clinical pharmacology of alosetron. Aliment Pharmacol Ther. 1999 May;13 Suppl 2:70-6. Pubmed
  7. Balfour JA, Goa KL, Perry CM: Alosetron. Drugs. 2000 Mar;59(3):511-8; discussion 519-20. Pubmed
  8. Camilleri M: Pharmacology and clinical experience with alosetron. Expert Opin Investig Drugs. 2000 Jan;9(1):147-59. Pubmed
  9. Rahimi R, Nikfar S, Abdollahi M: Efficacy and tolerability of alosetron for the treatment of irritable bowel syndrome in women and men: a meta-analysis of eight randomized, placebo-controlled, 12-week trials. Clin Ther. 2008 May;30(5):884-901. Pubmed
  10. Lewis JH: Alosetron for severe diarrhea-predominant irritable bowel syndrome: safety and efficacy in perspective. Expert Rev Gastroenterol Hepatol. 2010 Feb;4(1):13-29. Pubmed
  11. Andresen V, Hollerbach S: Reassessing the benefits and risks of alosetron: what is its place in the treatment of irritable bowel syndrome? Drug Saf. 2004;27(5):283-92. Pubmed

Enzymes

1. Cytochrome P450 2C9

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 2C9 P11712 Details

References:

  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

2. Cytochrome P450 3A4

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 3A4 P08684 Details

References:

  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

3. Cytochrome P450 1A2

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 1A2 P05177 Details

References:

  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

4. Cytochrome P450 2E1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Cytochrome P450 2E1 P05181 Details

References:

  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

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