Alosetron

Identification

Summary

Alosetron is a 5-HT3 antagonist used to treat diarrhea-predominant IBS.

Brand Names

Lotronex

Generic Name

Alosetron

DrugBank Accession Number

DB00969

Background

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 Alosetron was voluntarily withdrawn from the US market in November 2000 by the manufacturer due to numerous reports of severe adverse effects including ischemic colitis, severely obstructed or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.

Type

Small Molecule

Groups

Approved, Withdrawn

Structure

Similar Structures

Weight: Average: 294.351
Monoisotopic: 294.148061218
Chemical Formula: C₁₇H₁₈N₄O

Synonyms

2,3,4,5-Tetrahydro-5-methyl-2-((5-methyl-1H-imidazol-4-yl)methyl)-1H-pyrido(4,3-b)indol-1-one
Alosetron

External IDs

GR 68755
GR68755

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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.

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Associated Conditions

Indication Type	Indication	Combined Product Details	Approval Level	Age Group	Patient Characteristics	Dose Form
Management of	Severe diarrhea predominant irritable bowel syndrome		••••••••••••

Contraindications & Blackbox Warnings

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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.

Target	Actions	Organism
A5-hydroxytryptamine receptor 3A	antagonist	Humans

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

Adverse Effects

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Toxicity

Not Available

Pathways

Not Available

Pharmacogenomic Effects/ADRs Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">

Not Available

Interactions

Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">

This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.

Drug	Interaction
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1,2-Benzodiazepine	The risk or severity of CNS depression can be increased when Alosetron is combined with 1,2-Benzodiazepine.
Abametapir	The serum concentration of Alosetron can be increased when it is combined with Abametapir.
Abatacept	The metabolism of Alosetron can be increased when combined with Abatacept.
Abiraterone	The serum concentration of Alosetron can be increased when it is combined with Abiraterone.
Abrocitinib	The metabolism of Abrocitinib can be decreased when combined with Alosetron.

Food Interactions

Take with or without food. The absorption is unaffected by food.

Products

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Product Ingredients

Ingredient	UNII	CAS	InChI Key
Alosetron hydrochloride	2F5R1A46YW	122852-69-1	FNYQZOVOVDSGJH-UHFFFAOYSA-N

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
Lotronex	Tablet	0.5 mg/1	Oral	Prometheus Laboratories	2009-02-09	Not applicable
Lotronex	Tablet	0.5 mg/1	Oral	Sebela Pharmaceuticals Inc.	2016-07-11	Not applicable
Lotronex	Tablet	1 mg/1	Oral	Glaxosmithkline Inc	2000-02-09	2008-07-24
Lotronex	Tablet	1.0 mg/1	Oral	Prometheus Laboratories	2009-02-09	Not applicable
Lotronex	Tablet	0.5 mg/1	Oral	Glaxosmithkline Inc	2000-02-09	2009-09-24

Generic Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
Alosetron	Tablet	1 mg/1	Oral	Lifestar Pharma Llc	2020-09-14	Not applicable
Alosetron	Tablet	0.5 mg/1	Oral	bryant ranch prepack	2020-09-14	Not applicable
Alosetron	Tablet	0.5 mg/1	Oral	Lifestar Pharma Llc	2020-09-14	Not applicable
Alosetron	Tablet	1 mg/1	Oral	bryant ranch prepack	2020-09-14	Not applicable
Alosetron Hydrochloride	Tablet	0.5 mg/1	Oral	Par Pharmaceutical, Inc.	2019-04-05	Not applicable

Chemical Identifiers

UNII: 13Z9HTH115
CAS number: 122852-42-0
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

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

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. [Article]
Camilleri M: Pharmacology and clinical experience with alosetron. Expert Opin Investig Drugs. 2000 Jan;9(1):147-59. [Article]
Mayer EA, Bradesi S: Alosetron and irritable bowel syndrome. Expert Opin Pharmacother. 2003 Nov;4(11):2089-98. [Article]
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. [Article]
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. [Article]

External Links

Human Metabolome Database: HMDB0015104
KEGG Drug: D07129
PubChem Compound: 2099
PubChem Substance: 46506274
ChemSpider: 2015
BindingDB: 50014558
RxNav: 85248
ChEBI: 253342
ChEMBL: CHEMBL1110
ZINC: ZINC000013537284
Therapeutic Targets Database: DAP000369
PharmGKB: PA164745502
Guide to Pharmacology: GtP Drug Page
PDBe Ligand: S7Y
RxList: RxList Drug Page
Drugs.com: Drugs.com Drug Page
Wikipedia: Alosetron

PDB Entries

6w1j

FDA label

Download (208 KB)

Clinical Trials

Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">

Phase	Status	Purpose	Conditions	Count
4	Completed	Treatment	Irritable Bowel Syndrome (IBS)	1
3	Completed	Treatment	Irritable Bowel Syndrome (IBS)	2
2	Completed	Treatment	Irritable Bowel Syndrome (IBS)	1

Pharmacoeconomics

Manufacturers

Prometheus laboratories inc

Packagers

GlaxoSmithKline Inc.
Prometheus Laboratories Inc.

Dosage Forms

Form	Route	Strength
Tablet, film coated	Oral	0.5 mg/1
Tablet, film coated	Oral	1 mg/1
Tablet	Oral	0.5 mg/1
Tablet	Oral	1 mg/1
Tablet	Oral	1.0 mg/1

Prices

Unit description	Cost	Unit
Lotronex 1 mg tablet	19.47USD	tablet
Lotronex 0.5 mg tablet	14.3USD	tablet

DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
US5360800	No	1994-11-01	2013-01-13
US6284770	No	2001-09-04	2018-10-05

Properties

State

Solid

Experimental Properties

Property	Value	Source
logP	2	Not Available

Predicted Properties

Property	Value	Source
Water Solubility	0.438 mg/mL	ALOGPS
logP	1.85	ALOGPS
logP	1.21	Chemaxon
logS	-2.8	ALOGPS
pKa (Strongest Acidic)	13.32	Chemaxon
pKa (Strongest Basic)	6.81	Chemaxon
Physiological Charge	0	Chemaxon
Hydrogen Acceptor Count	2	Chemaxon
Hydrogen Donor Count	1	Chemaxon
Polar Surface Area	53.92 Å²	Chemaxon
Rotatable Bond Count	2	Chemaxon
Refractivity	86.41 m³·mol^-1	Chemaxon
Polarizability	32.52 Å³	Chemaxon
Number of Rings	4	Chemaxon
Bioavailability	1	Chemaxon
Rule of Five	Yes	Chemaxon
Ghose Filter	Yes	Chemaxon
Veber's Rule	No	Chemaxon
MDDR-like Rule	No	Chemaxon

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 inhibitor	Non-inhibitor	0.8878
CYP450 2D6 inhibitor	Inhibitor	0.6507
CYP450 2C19 inhibitor	Non-inhibitor	0.9239
CYP450 3A4 inhibitor	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

ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted GC-MS Spectrum - GC-MS	Predicted GC-MS	splash10-054p-9640000000-36ec950b2b5a4de0d766
MS/MS Spectrum - , positive	LC-MS/MS	splash10-0udi-0390000000-3b813a9458d2bce7516f
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	splash10-0006-0290000000-15bddd47f373eb667d36
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	splash10-0002-0090000000-ea8da26c53a0e796404d
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	splash10-0002-0090000000-ae47caffe1cf52321d57
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	splash10-0007-1190000000-de5347291a022e684281
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	splash10-03ed-4790000000-f8cd452d5238f9e29fdb
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	splash10-05al-2950000000-19fb31d533c50402f31b
Predicted 1H NMR Spectrum	1D NMR	Not Applicable
Predicted 13C NMR Spectrum	1D NMR	Not Applicable

Chromatographic Properties

Collision Cross Sections (CCS)

Adduct	CCS Value (Å²)	Source type	Source
[M-H]-	180.1968973	predicted	DarkChem Lite v0.1.0
[M-H]-	181.2782973	predicted	DarkChem Lite v0.1.0
[M-H]-	164.76216	predicted	DeepCCS 1.0 (2019)
[M+H]+	180.8015973	predicted	DarkChem Lite v0.1.0
[M+H]+	180.7651973	predicted	DarkChem Lite v0.1.0
[M+H]+	167.12016	predicted	DeepCCS 1.0 (2019)
[M+Na]+	179.9657973	predicted	DarkChem Lite v0.1.0
[M+Na]+	181.2261973	predicted	DarkChem Lite v0.1.0
[M+Na]+	173.21332	predicted	DeepCCS 1.0 (2019)

Targets

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insights and accelerate drug research.

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Property	Measurement	pH	Temperature (°C)	References
Ki (nM)	0.5	N/A	N/A	A29199 / A29246

Details1. 5-hydroxytryptamine receptor 3A

Kind: Protein
Organism: Humans
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

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. [Article]
Mayer EA, Bradesi S: Alosetron and irritable bowel syndrome. Expert Opin Pharmacother. 2003 Nov;4(11):2089-98. [Article]
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. [Article]
Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
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. [Article]
Gunput MD: Review article: clinical pharmacology of alosetron. Aliment Pharmacol Ther. 1999 May;13 Suppl 2:70-6. [Article]
Balfour JA, Goa KL, Perry CM: Alosetron. Drugs. 2000 Mar;59(3):511-8; discussion 519-20. [Article]
Camilleri M: Pharmacology and clinical experience with alosetron. Expert Opin Investig Drugs. 2000 Jan;9(1):147-59. [Article]
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. [Article]
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. [Article]
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. [Article]

Enzymes

Details1. Cytochrome P450 1A2

Kind: Protein
Organism: Humans
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

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. [Article]
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. [Article]
Lucak SL: Optimizing outcomes with alosetron hydrochloride in severe diarrhea-predominant irritable bowel syndrome. Therap Adv Gastroenterol. 2010 May;3(3):165-72. doi: 10.1177/1756283X10362277. [Article]
Alosteron [Link]
Alosteron FDA label [File]
CTEP CYP1A2 document, NIH [File]

Property	Measurement	pH	Temperature (°C)	References
IC 50 (nM)	600	N/A	N/A	A29199 / A29246

Details2. Cytochrome P450 3A4

Kind: Protein
Organism: Humans
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

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. [Article]
Alosetron FDA label [Link]

Details3. Cytochrome P450 2C9

Kind: Protein
Organism: Humans
Pharmacological action: No
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

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. [Article]
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. [Article]

Details4. Cytochrome P450 2E1

Kind: Protein
Organism: Humans
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

LOTRONEX (alosetron hydrochloride) Tablets - FDA Label [Link]
List of drugs that may have potential CYP2E1 interactions [File]

Drug created at June 13, 2005 13:24 / Updated at February 02, 2024 22:46

Alosetron

Identification

Structure for Alosetron (DB00969)

Pharmacology

Interactions

Products

Categories

Chemical Identifiers

References

Clinical Trials

Pharmacoeconomics

Properties

Spectra

Collision Cross Sections (CCS)

Targets

References

Enzymes

References

References

References

References