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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GroupsApproved, Withdrawn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 Alosetron was voluntarily withdrawn from the US market in November 2000 by the manufacturer due to numerous reports of severe adverse effects including ischemic colitis, severely obstructed or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
2,3,4,5-Tetrahydro-5-methyl-2-((5-methyl-1H-imidazol-4-yl)methyl)-1H-pyrido(4,3-b)indol-1-one
External Identifiers Not Available
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Alosetron Hydrochloridetablet.5 mg/1oralActavis Pharma, Inc.2015-05-26Not applicableUs
Alosetron Hydrochloridetablet1 mg/1oralActavis Pharma, Inc.2015-05-26Not applicableUs
Lotronextablet1 mg/1oralPrometheus Laboratories Inc.2009-02-09Not applicableUs
Lotronextablet.5 mg/1oralPrometheus Laboratories Inc.2009-02-09Not applicableUs
Approved Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Alosetron Hydrochloridetablet.5 mg/1oralRoxane Laboratories, Inc.2013-07-15Not applicableUs
Alosetron Hydrochloridetablet1 mg/1oralRoxane Laboratories, Inc.2013-07-15Not applicableUs
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International BrandsNot Available
Brand mixturesNot Available
Salts
Name/CASStructureProperties
Alosetron Hydrochloride
122852-69-1
Thumb
  • InChI Key: FNYQZOVOVDSGJH-UHFFFAOYSA-N
  • Monoisotopic Mass: 330.124738957
  • Average Mass: 330.812
DBSALT000247
Categories
UNII13Z9HTH115
CAS number122852-42-0
WeightAverage: 294.351
Monoisotopic: 294.148061218
Chemical FormulaC17H18N4O
InChI KeyInChIKey=JSWZEAMFRNKZNL-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
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as indoles. These are compounds containing an indole moiety, which consists of pyrrole ring fused to benzene to form 2,3-benzopyrrole.
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassIndoles and derivatives
Sub ClassIndoles
Direct ParentIndoles
Alternative Parents
Substituents
  • Indole
  • Benzenoid
  • Substituted pyrrole
  • N-methylpyrrole
  • Heteroaromatic compound
  • Vinylogous amide
  • Pyrrole
  • Imidazole
  • Azole
  • Tertiary amine
  • Lactam
  • Carboxamide group
  • Azacycle
  • Carboxylic acid derivative
  • Hydrocarbon derivative
  • Organooxygen compound
  • Organonitrogen compound
  • Carbonyl group
  • Amine
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External Descriptors
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.
Related Articles
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
PropertyValueProbability
Human Intestinal Absorption+0.9745
Blood Brain Barrier+0.9139
Caco-2 permeable+0.6511
P-glycoprotein substrateSubstrate0.8033
P-glycoprotein inhibitor IInhibitor0.7435
P-glycoprotein inhibitor IINon-inhibitor0.5707
Renal organic cation transporterInhibitor0.7795
CYP450 2C9 substrateNon-substrate0.7501
CYP450 2D6 substrateNon-substrate0.9116
CYP450 3A4 substrateSubstrate0.7672
CYP450 1A2 substrateNon-inhibitor0.5781
CYP450 2C9 inhibitorNon-inhibitor0.8878
CYP450 2D6 inhibitorInhibitor0.6507
CYP450 2C19 inhibitorNon-inhibitor0.9239
CYP450 3A4 inhibitorNon-inhibitor0.8274
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.6424
Ames testNon AMES toxic0.6156
CarcinogenicityNon-carcinogens0.967
BiodegradationNot ready biodegradable0.981
Rat acute toxicity2.7709 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.8334
hERG inhibition (predictor II)Inhibitor0.8554
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
Manufacturers
  • Prometheus laboratories inc
Packagers
Dosage forms
FormRouteStrength
Tabletoral.5 mg/1
Tabletoral1 mg/1
Prices
Unit descriptionCostUnit
Lotronex 1 mg tablet19.47USD tablet
Lotronex 0.5 mg tablet14.3USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US5360800 No1993-01-132013-01-13Us
US6284770 No1998-10-052018-10-05Us
Properties
StateSolid
Experimental Properties
PropertyValueSource
logP2Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.438 mg/mLALOGPS
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 RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
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 References
  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:15061683 ]
  2. Camilleri M: Pharmacology and clinical experience with alosetron. Expert Opin Investig Drugs. 2000 Jan;9(1):147-59. [PubMed:11060667 ]
  3. Mayer EA, Bradesi S: Alosetron and irritable bowel syndrome. Expert Opin Pharmacother. 2003 Nov;4(11):2089-98. [PubMed:14596662 ]
  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. doi: 10.1016/j.clinthera.2008.05.002. [PubMed:18555935 ]
  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. doi: 10.1586/egh.09.72. [PubMed:20136586 ]
External Links
ATC CodesA03AE01
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelDownload (208 KB)
MSDSNot Available
Interactions
Drug Interactions
Drug
AbirateroneThe serum concentration of Alosetron can be increased when it is combined with Abiraterone.
ApomorphineAlosetron may increase the hypotensive activities of Apomorphine.
AtazanavirThe serum concentration of Alosetron can be increased when it is combined with Atazanavir.
BoceprevirThe serum concentration of Alosetron can be increased when it is combined with Boceprevir.
BortezomibThe metabolism of Alosetron can be decreased when combined with Bortezomib.
CeritinibThe serum concentration of Alosetron can be increased when it is combined with Ceritinib.
ClarithromycinThe serum concentration of Alosetron can be increased when it is combined with Clarithromycin.
CobicistatThe serum concentration of Alosetron can be increased when it is combined with Cobicistat.
DarunavirThe serum concentration of Alosetron can be increased when it is combined with Darunavir.
DeferasiroxThe serum concentration of Alosetron can be increased when it is combined with Deferasirox.
EluxadolineAlosetron may increase the activities of Eluxadoline.
FluvoxamineThe metabolism of Alosetron can be decreased when combined with Fluvoxamine.
IdelalisibThe serum concentration of Alosetron can be increased when it is combined with Idelalisib.
IndinavirThe serum concentration of Alosetron can be increased when it is combined with Indinavir.
ItraconazoleThe serum concentration of Alosetron can be increased when it is combined with Itraconazole.
KetoconazoleThe serum concentration of Alosetron can be increased when it is combined with Ketoconazole.
MexiletineThe metabolism of Alosetron can be decreased when combined with Mexiletine.
NefazodoneThe serum concentration of Alosetron can be increased when it is combined with Nefazodone.
NelfinavirThe serum concentration of Alosetron can be increased when it is combined with Nelfinavir.
Peginterferon alfa-2bThe serum concentration of Alosetron can be increased when it is combined with Peginterferon alfa-2b.
PosaconazoleThe serum concentration of Alosetron can be increased when it is combined with Posaconazole.
RitonavirThe serum concentration of Alosetron can be increased when it is combined with Ritonavir.
SaquinavirThe serum concentration of Alosetron can be increased when it is combined with Saquinavir.
TapentadolAlosetron may decrease the analgesic activities of Tapentadol.
TelaprevirThe serum concentration of Alosetron can be increased when it is combined with Telaprevir.
TelithromycinThe serum concentration of Alosetron can be increased when it is combined with Telithromycin.
TramadolAlosetron may decrease the analgesic activities of Tramadol.
VemurafenibThe serum concentration of Alosetron can be increased when it is combined with Vemurafenib.
VoriconazoleThe serum concentration of Alosetron can be increased when it is combined with Voriconazole.
Food Interactions
  • Absorption is decreased by about 25% when taken with meals.
  • Take without regard to meals.

Targets

Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
antagonist
General Function:
Voltage-gated potassium channel activity
Specific Function:
This is one of the several different receptors for 5-hydroxytryptamine (serotonin), a biogenic hormone that functions as a neurotransmitter, a hormone, and a mitogen. This receptor is a ligand-gated ion channel, which when activated causes fast, depolarizing responses in neurons. It is a cation-specific, but otherwise relatively nonselective, ion channel.
Gene Name:
HTR3A
Uniprot ID:
P46098
Molecular Weight:
55279.835 Da
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:10354345 ]
  2. Mayer EA, Bradesi S: Alosetron and irritable bowel syndrome. Expert Opin Pharmacother. 2003 Nov;4(11):2089-98. [PubMed:14596662 ]
  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:17138606 ]
  4. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352 ]
  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:10848662 ]
  6. Gunput MD: Review article: clinical pharmacology of alosetron. Aliment Pharmacol Ther. 1999 May;13 Suppl 2:70-6. [PubMed:10429744 ]
  7. Balfour JA, Goa KL, Perry CM: Alosetron. Drugs. 2000 Mar;59(3):511-8; discussion 519-20. [PubMed:10776833 ]
  8. Camilleri M: Pharmacology and clinical experience with alosetron. Expert Opin Investig Drugs. 2000 Jan;9(1):147-59. [PubMed:11060667 ]
  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. doi: 10.1016/j.clinthera.2008.05.002. [PubMed:18555935 ]
  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. doi: 10.1586/egh.09.72. [PubMed:20136586 ]
  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:15061683 ]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
Specific Function:
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. Most active in catalyzing 2-hydroxylation. Caffeine is metabolized primarily by cytochrome CYP1A2 in the liver through an initial N...
Gene Name:
CYP1A2
Uniprot ID:
P05177
Molecular Weight:
58293.76 Da
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. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Steroid hydroxylase activity
Specific Function:
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. This enzyme contributes to the wide pharmacokinetics variability of the metabolism of drugs such as S-warfarin, diclofenac, phenyto...
Gene Name:
CYP2C9
Uniprot ID:
P11712
Molecular Weight:
55627.365 Da
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. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Vitamin d3 25-hydroxylase activity
Specific Function:
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4-hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiot...
Gene Name:
CYP3A4
Uniprot ID:
P08684
Molecular Weight:
57342.67 Da
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. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inhibitor
General Function:
Steroid hydroxylase activity
Specific Function:
Metabolizes several precarcinogens, drugs, and solvents to reactive metabolites. Inactivates a number of drugs and xenobiotics and also bioactivates many xenobiotic substrates to their hepatotoxic or carcinogenic forms.
Gene Name:
CYP2E1
Uniprot ID:
P05181
Molecular Weight:
56848.42 Da
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. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256 ]
Comments
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Drug created on June 13, 2005 07:24 / Updated on May 25, 2016 02:16