Identification

Name
Alosetron
Accession Number
DB00969  (APRD00580)
Type
Small Molecule
Groups
Approved, Withdrawn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 Alosetron was voluntarily withdrawn from the US market in November 2000 by the manufacturer due to numerous reports of severe adverse effects including ischemic colitis, severely obstructed or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 IDs
A03AE01
Product Ingredients
IngredientUNIICASInChI Key
Alosetron Hydrochloride2F5R1A46YW122852-69-1FNYQZOVOVDSGJH-UHFFFAOYSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Alosetron HydrochlorideTablet1 mg/1OralActavis Pharma Company2015-05-26Not applicableUs
Alosetron HydrochlorideTablet0.5 mg/1OralActavis Pharma Company2015-05-26Not applicableUs
LotronexTablet1.0 mg/1OralPrometheus Laboratories2009-02-09Not applicableUs
LotronexTablet0.5 mg/1OralGlaxosmithkline Inc2000-02-092009-09-24Us
LotronexTablet1 mg/1OralSebela Pharmaceuticals Inc.2016-07-11Not applicableUs
LotronexTablet0.5 mg/1OralPrometheus Laboratories2009-02-09Not applicableUs
LotronexTablet0.5 mg/1OralSebela Pharmaceuticals Inc.2016-07-11Not applicableUs
LotronexTablet1 mg/1OralGlaxosmithkline Inc2000-02-092008-07-24Us
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Alosetron HydrochlorideTablet, film coated1 mg/1OralAmneal Pharmaceuticals2017-01-02Not applicableUs
Alosetron HydrochlorideTablet0.5 mg/1OralWest-Ward Pharmaceuticals Corp.2013-07-15Not applicableUs
Alosetron HydrochlorideTablet1 mg/1OralPar Pharmaceutical2018-02-16Not applicableUs
Alosetron HydrochlorideTablet, film coated0.5 mg/1OralAmneal Pharmaceuticals2017-01-02Not applicableUs
Alosetron HydrochlorideTablet, film coated1 mg/1OralAv Kare, Inc.2017-02-23Not applicableUs
Alosetron HydrochlorideTablet0.5 mg/1OralPar Pharmaceutical2018-02-16Not applicableUs
Alosetron HydrochlorideTablet1 mg/1OralWest-Ward Pharmaceuticals Corp.2013-07-15Not applicableUs
Alosetron HydrochlorideTablet, film coated0.5 mg/1OralAv Kare, Inc.2017-02-23Not applicableUs
Categories
UNII
13Z9HTH115
CAS number
122852-42-0
Weight
Average: 294.351
Monoisotopic: 294.148061218
Chemical Formula
C17H18N4O
InChI Key
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

Pharmacology

Indication

Only 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.

Associated Conditions
Pharmacodynamics

Alosetron 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 action

Alosetron 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.

TargetActionsOrganism
A5-hydroxytryptamine receptor 3A
antagonist
Human
Absorption

50-60 %

Volume of distribution
  • 65 to 95 L
Protein binding

82%

Metabolism

Hepatic, via microsomal cytochrome P450 (CYP)

Route of elimination

Renal elimination of unchanged alosetron accounts for only 6% of the dose. Alosetron is extensively metabolized in humans.

Half life

1.5 hours

Clearance
  • 600 mL/min
Toxicity
Not Available
Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe metabolism of (R)-warfarin can be decreased when combined with Alosetron.
(S)-WarfarinThe risk or severity of adverse effects can be increased when Alosetron is combined with (S)-Warfarin.
2,5-Dimethoxy-4-ethylthioamphetamineThe risk or severity of adverse effects can be increased when Alosetron is combined with 2,5-Dimethoxy-4-ethylthioamphetamine.
3-isobutyl-1-methyl-7H-xanthineThe serum concentration of 3-isobutyl-1-methyl-7H-xanthine can be increased when it is combined with Alosetron.
3,4-MethylenedioxyamphetamineThe risk or severity of adverse effects can be increased when Alosetron is combined with 3,4-Methylenedioxyamphetamine.
3,5-diiodothyropropionic acidThe metabolism of 3,5-diiodothyropropionic acid can be decreased when combined with Alosetron.
4-Bromo-2,5-dimethoxyamphetamineThe risk or severity of adverse effects can be increased when Alosetron is combined with 4-Bromo-2,5-dimethoxyamphetamine.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be decreased when combined with Alosetron.
4-MethoxyamphetamineThe risk or severity of adverse effects can be increased when Alosetron is combined with 4-Methoxyamphetamine.
5-androstenedioneThe metabolism of 5-androstenedione can be decreased when combined with Alosetron.
Food Interactions
  • Absorption is decreased by about 25% when taken with meals.
  • Take without regard to meals.

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
Human Metabolome Database
HMDB0015104
PubChem Compound
2099
PubChem Substance
46506274
ChemSpider
2015
BindingDB
50014558
ChEBI
253342
ChEMBL
CHEMBL1110
Therapeutic Targets Database
DAP000369
PharmGKB
PA164745502
IUPHAR
2296
Guide to Pharmacology
GtP Drug Page
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Alosetron
ATC Codes
A03AE01 — Alosetron
FDA label
Download (208 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2CompletedTreatmentIrritable Bowel Syndrome (IBS)1
3CompletedTreatmentIrritable Bowel Syndrome (IBS)2
4CompletedTreatmentIrritable Bowel Syndrome (IBS)1

Pharmacoeconomics

Manufacturers
  • Prometheus laboratories inc
Packagers
  • GlaxoSmithKline Inc.
  • Prometheus Laboratories Inc.
Dosage forms
FormRouteStrength
Tablet, film coatedOral0.5 mg/1
Tablet, film coatedOral1 mg/1
TabletOral0.5 mg/1
TabletOral1 mg/1
TabletOral1.0 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)
US5360800No1993-01-132013-01-13Us
US6284770No1998-10-052018-10-05Us

Properties

State
Solid
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 RuleNoChemAxon
MDDR-like RuleNoChemAxon
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)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available
MS/MS Spectrum - , positiveLC-MS/MSsplash10-0udi-0390000000-3b813a9458d2bce7516f

Taxonomy

Description
This compound belongs to the class of organic compounds known as n-alkylindoles. These are compounds containing an indole moiety that carries an alkyl chain at the 1-position.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Indoles and derivatives
Sub Class
N-alkylindoles
Direct Parent
N-alkylindoles
Alternative Parents
Indoles / N-methylpyrroles / Benzenoids / Vinylogous amides / Tertiary carboxylic acid amides / Imidazoles / Heteroaromatic compounds / Lactams / Azacyclic compounds / Organopnictogen compounds
show 4 more
Substituents
N-alkylindole / Indole / N-methylpyrrole / Substituted pyrrole / Benzenoid / Imidazole / Heteroaromatic compound / Pyrrole / Vinylogous amide / Azole
show 13 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
imidazoles, pyridoindole (CHEBI:253342)

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-gate...
Gene Name
HTR3A
Uniprot ID
P46098
Uniprot Name
5-hydroxytryptamine receptor 3A
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
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
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]
  2. D'Souza DL, Dimmitt DC, Robbins DK, Nezamis J, Simms L, Koch KM: Effect of alosetron on the pharmacokinetics of fluoxetine. J Clin Pharmacol. 2001 Apr;41(4):455-8. [PubMed:11304903]
  3. D'Souza DL, Levasseur LM, Nezamis J, Robbins DK, Simms L, Koch KM: Effect of alosetron on the pharmacokinetics of alprazolam. J Clin Pharmacol. 2001 Apr;41(4):452-4. [PubMed:11304902]
Details
2. Cytochrome P450 3A4
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 react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
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
Substrate
Inhibitor
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 un...
Gene Name
CYP1A2
Uniprot ID
P05177
Uniprot Name
Cytochrome P450 1A2
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]
  2. Wang B, Zhou SF: Synthetic and natural compounds that interact with human cytochrome P450 1A2 and implications in drug development. Curr Med Chem. 2009;16(31):4066-218. [PubMed:19754423]
  3. Koch KM, Corrigan BW, Manzo J, James CD, Scott RJ, Stead AG, Kersey KE: Alosetron repeat dose pharmacokinetics, effects on enzyme activities, and influence of demographic factors. Aliment Pharmacol Ther. 2004 Jul 15;20(2):223-30. doi: 10.1111/j.1365-2036.2004.02031.x. [PubMed:15233703]
  4. Alosteron [Link]
  5. Alosteron FDA label [File]
  6. CTEP CYP1A2 document, NIH [File]
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 ...
Gene Name
CYP2E1
Uniprot ID
P05181
Uniprot Name
Cytochrome P450 2E1
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]
  2. List of drugs that may have potential CYP2E1 interactions [File]

Drug created on June 13, 2005 07:24 / Updated on November 02, 2018 08:36