Lubiprostone

Identification

Summary

Lubiprostone is a prostaglandin derivative used to treat constipation caused by irritable bowel syndrome and opioid-use.

Brand Names

Amitiza

Generic Name

Lubiprostone

DrugBank Accession Number

DB01046

Background

Lubiprostone is a medication used in the management of idiopathic chronic constipation. A prostaglandin E1 derivative, lubiprostone is a bicyclic fatty acid that activates ClC-2 chloride channels located on the apical side of the gastrointestinal epithelial cells. Activation of these channels promotes the secretion of a chloride-rich fluid that soften the stool, increase gastrointestinal motility, and induce spontaneous bowel movements (SBM).

Type

Small Molecule

Groups

Approved, Investigational

Structure

3D

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MOLSDF3D-SDFPDBSMILESInChI

Similar Structures

Structure for Lubiprostone (DB01046)

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Weight

Average: 390.468
Monoisotopic: 390.221780456

Chemical Formula

C₂₀H₃₂F₂O₅

Synonyms

• Lubiprostone

External IDs

• RU-0211

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Pharmacology

Indication

Lubiprostone is indicated for the treatment of adult patients with chronic idiopathic constipation, or opioid-induced constipation in patients with chronic non-cancer pain.⁵ It is also indicated for the treatment of irritable bowel syndrome with constipation (IBS-C) in female patients ≥18 years old.⁵

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Associated Conditions

Indication Type	Indication	Combined Product Details	Approval Level	Age Group	Patient Characteristics	Dose Form
Treatment of	Chronic idiopathic constipation		••••••••••••	•••••		•••••••
Treatment of	Constipation-predominant irritable bowel syndrome (ibs-c)		••••••••••••			•••••••
Treatment of	Opioid induced constipation		••••••••••••	•••••	••••••• ••••••••• ••••	•••••••

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Pharmacodynamics

Chronic idiopathic constipation is generally defined by infrequent or difficult passage of stool. The signs and symptoms associated with chronic idiopathic constipation (i.e., abdominal pain or discomfort, bloating, straining, and hard or lumpy stools) may be the result of abnormal colonic motility that can delay the transit of intestinal contents and impede the evacuation of rectal contents. One approach to the treatment of chronic idiopathic constipation is the secretion of fluid into the abdominal lumen through the activation of chloride channels in the apical membrane of the gastrointestinal epithelium. Lubiprostone is a locally acting chloride channel activator that increases intestinal chloride and fluid secretion without altering sodium and potassium concentrations in the serum.

Mechanism of action

Lubiprostone acts by specifically activating ClC-2 chloride channels, which is a normal constituent of the apical membrane of the human intestine, in a protein kinase A action independent fashion. Activation of ClC-2 chloride channels causes an efflux of chloride ions into the lumen, which in turn leads to an efflux of sodium ions through a paracellular pathway to maintain isoelectric neutrality. As a result, water follows sodium into the lumen in order to maintain isotonic equilibrium, thereby increasing intestinal fluid secretion. By increasing intestinal fluid secretion, lubiprostone increases motility in the intestine, thereby increasing the passage of stool and alleviating symptoms associated with chronic idiopathic constipation. Activation of ClC-2 chloride channels may also stimulate the recovery of muscosal barrier function by restoring tight junction protein complexes in the intestine. Patch clamp cell studies in human cell lines have indicated that the majority of the beneficial biological activity of lubiprostone and its metabolites is observed only on the apical (luminal) portion of the gastrointestinal epithelium.

Target	Actions	Organism
AChloride channel protein 2	inducer	Humans

Absorption

Lubiprostone has low systemic availability following oral administration and concentrations of lubiprostone in plasma are below the level of quantitation (10 pg/mL).

Volume of distribution

Not Available

Protein binding

94%

Metabolism

The results of both human and animal studies indicate that lubiprostone is rapidly and extensively metabolized by 15-position reduction, α-chain β-oxidation, and ω-chain ω-oxidation. These biotransformations are not mediated by the hepatic cytochrome P450 system but rather appear to be mediated by the ubiquitously expressed carbonyl reductase. M3, a metabolite of lubiprostone in both humans and animals is formed by the reduction of the carbonyl group at the 15-hydroxy moiety that consists of both α-hydroxy and β-hydroxy epimers. M3 makes up less than 10% of the dose of radiolabeled lubiprostone.

Route of elimination

Peak plasma concentration was shown to be around 1.14 hours, with a majority of the drug excreted in the urine within 48 hours. Lubiprostone and M3 are only detected in trace amounts in human feces.

Half-life

0.9 to 1.4 hours

Clearance

Not Available

Adverse Effects

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Toxicity

In a definitive Phase 1 cardiac repolarization study, 51 patients were administered a single oral dose of 144 mcg of lubiprostone, which is 6 times the normal single administration dose. Thirty-nine (39) of the 51 patients experienced an adverse event. The adverse events reported in >1% of this group included the following: nausea (45.1%), vomiting (27.5%), diarrhea (25.5%), dizziness (17.6%), loose or watery stools (13.7%), headache (11.8%), retching (7.8%), abdominal pain (5.9%), flushing or hot flush (5.9%), dyspnea (3.9%), pallor (3.9%), stomach discomfort (3.9%), syncope (3.9%), upper abdominal pain (2.0%), anorexia (2.0%), asthenia (2.0%), chest discomfort (2.0%), dry mouth (2.0%), hyperhidrosis (2.0%), skin irritation (2.0%) and vasovagal episode (2.0%).

Pathways

Not Available

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Not Available

Interactions

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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.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
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Abacavir	Lubiprostone may decrease the excretion rate of Abacavir which could result in a higher serum level.
Aceclofenac	Aceclofenac may decrease the excretion rate of Lubiprostone which could result in a higher serum level.
Acemetacin	Acemetacin may decrease the excretion rate of Lubiprostone which could result in a higher serum level.
Acetaminophen	Acetaminophen may decrease the excretion rate of Lubiprostone which could result in a higher serum level.
Acetazolamide	The risk or severity of dehydration can be increased when Acetazolamide is combined with Lubiprostone.

Food Interactions

• Take with a full glass of water.
• Take with food. Taking lubiprostone with food may reduce nausea.

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Product Images

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Amitiza	Capsule	24 mcg	Oral	Sucampo Pharma Americas, Llc	Not applicable	Not applicable
Amitiza	Capsule, gelatin coated	8 ug/1	Oral	Takeda Pharmaceuticals America, Inc.	2006-01-31	Not applicable
Amitiza	Capsule, gelatin coated	24 ug/1	Oral	Carilion Materials Management	2006-01-31	Not applicable
Amitiza	Capsule, gelatin coated	8 ug/1	Oral	Stat Rx USA	2006-01-31	Not applicable
Amitiza	Capsule, gelatin coated	8 ug/1	Oral	Avera McKennan Hospital	2015-04-06	2017-05-24

Generic Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Amitza	Capsule, gelatin coated	8 ug/1	Oral	Direct_Rx	2023-01-12	Not applicable
Lubiprostone	Capsule, gelatin coated	8 ug/1	Oral	Sun Pharmaceutical Industries, Inc.	2023-01-01	Not applicable
Lubiprostone	Capsule	8 ug/1	Oral	Zydus Pharmaceuticals USA Inc.	2023-03-23	Not applicable
Lubiprostone	Capsule	24 ug/1	Oral	Natco Pharma USA LLC	2022-10-17	Not applicable
Lubiprostone	Capsule	24 ug/1	Oral	Amneal Pharmaceuticals LLC	2021-12-03	Not applicable

Categories

ATC Codes

A06AX03 — Lubiprostone

• A06AX — Other drugs for constipation
• A06A — DRUGS FOR CONSTIPATION
• A06 — DRUGS FOR CONSTIPATION
• A — ALIMENTARY TRACT AND METABOLISM

Drug Categories

• Alimentary Tract and Metabolism
• Chloride Channel Agonists
• Drugs for Constipation
• Drugs that are Mainly Renally Excreted
• Fatty Acids
• Fatty Acids, Monounsaturated
• Fatty Acids, Unsaturated
• Laxatives
• Lipids
• Membrane Transport Modulators
• Miscellaneous GI Drugs
• Prostaglandins E

Chemical TaxonomyProvided by Classyfire

Description

This compound belongs to the class of organic compounds known as prostaglandins and related compounds. These are unsaturated carboxylic acids consisting of a 20 carbon skeleton that also contains a five member ring, and are based upon the fatty acid arachidonic acid.

Kingdom

Organic compounds

Super Class

Lipids and lipid-like molecules

Class

Fatty Acyls

Sub Class

Eicosanoids

Direct Parent

Prostaglandins and related compounds

Alternative Parents

Medium-chain fatty acids / Hydroxy fatty acids / Heterocyclic fatty acids / Halogenated fatty acids / Oxanes / Hemiacetals / Fluorohydrins / Cyclic ketones / Oxacyclic compounds / Monocarboxylic acids and derivatives / Carboxylic acids / Organofluorides / Organic oxides / Hydrocarbon derivatives / Alkyl fluorides

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Substituents

Aliphatic heteropolycyclic compound / Alkyl fluoride / Alkyl halide / Carbonyl group / Carboxylic acid / Carboxylic acid derivative / Cyclic ketone / Fatty acid / Fluorohydrin / Halogenated fatty acid / Halohydrin / Hemiacetal / Heterocyclic fatty acid / Hydrocarbon derivative / Hydroxy fatty acid / Ketone / Medium-chain fatty acid / Monocarboxylic acid or derivatives / Organic oxide / Organic oxygen compound / Organofluoride / Organohalogen compound / Organoheterocyclic compound / Organooxygen compound / Oxacycle / Oxane / Prostaglandin skeleton

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Molecular Framework

Aliphatic heteropolycyclic compounds

External Descriptors

Not Available

Affected organisms

• Humans and other mammals

Chemical Identifiers

UNII

7662KG2R6K

CAS number

136790-76-6

InChI Key

WGFOBBZOWHGYQH-MXHNKVEKSA-N

InChI

InChI=1S/C20H32F2O5/c1-2-3-11-19(21,22)20(26)12-10-15-14(16(23)13-17(15)27-20)8-6-4-5-7-9-18(24)25/h14-15,17,26H,2-13H2,1H3,(H,24,25)/t14-,15-,17-,20-/m1/s1

IUPAC Name

7-[(2R,4aR,5R,7aR)-2-(1,1-difluoropentyl)-2-hydroxy-6-oxo-octahydrocyclopenta[b]pyran-5-yl]heptanoic acid

SMILES

[H][C@@]12CC(=O)[C@H](CCCCCCC(O)=O)[C@@]1([H])CC[C@@](O)(O2)C(F)(F)CCCC

References

Synthesis Reference

Zhijun Tang, Zhonghao Zhuo, Yunman Zheng, Bingming He, Huichun Yang, Jushang Zheng, "LUBIPROSTONE CRYSTAL, THE USE AND THE METHOD FOR THE PREPARATION THEREOF." U.S. Patent US20110028541, issued February 03, 2011.

US20110028541

General References

1. Crowell MD, Harris LA, DiBaise JK, Olden KW: Activation of type-2 chloride channels: a novel therapeutic target for the treatment of chronic constipation. Curr Opin Investig Drugs. 2007 Jan;8(1):66-70. [Article]
2. Lacy BE, Chey WD: Lubiprostone: chronic constipation and irritable bowel syndrome with constipation. Expert Opin Pharmacother. 2009 Jan;10(1):143-52. doi: 10.1517/14656560802631319 . [Article]
3. Ambizas EM, Ginzburg R: Lubiprostone: a chloride channel activator for treatment of chronic constipation. Ann Pharmacother. 2007 Jun;41(6):957-64. Epub 2007 May 22. [Article]
4. Lacy BE, Levy LC: Lubiprostone: a novel treatment for chronic constipation. Clin Interv Aging. 2008;3(2):357-64. [Article]
5. FDA Approved Drug Products: Amitiza (lubiprostone) capsules for oral use [Link]

External Links

KEGG Drug

D04790

KEGG Compound

C13707

PubChem Compound

157920

PubChem Substance

46505874

ChemSpider

138948

RxNav

623033

ChEMBL

CHEMBL1201134

ZINC

ZINC000004217732

Therapeutic Targets Database

DAP000208

PharmGKB

PA164777012

Drugs.com

Drugs.com Drug Page

Wikipedia

Lubiprostone

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	Diagnostic	Indication for Modification of Patient Status (Diagnosis)	1
4	Completed	Diagnostic	Inflammatory Bowel Diseases (IBD)	1
4	Completed	Health Services Research	Chronic idiopathic constipation (CIC)	1
4	Completed	Treatment	Colonoscopy	2
4	Completed	Treatment	Constipation	2

Pharmacoeconomics

Manufacturers

Not Available

Packagers

• Catalent Pharma Solutions
• Stat Rx Usa
• Takeda Pharmaceutical Co. Ltd.

Dosage Forms

Form	Route	Strength
Capsule	Oral
Capsule, gelatin coated	Oral	24 ug/1
Capsule, gelatin coated	Oral	8 ug/1
Capsule, liquid filled	Oral	8 mcg
Capsule	Oral	24 ug/1
Capsule	Oral	8 ug/1
Capsule, liquid filled	Oral	24 mcg
Capsule	Oral	24 mcg
Capsule	Oral	8 mcg

Prices

Unit description	Cost	Unit
Amitiza 8 mcg capsule	4.27USD	capsule
Amitiza 24 mcg capsule	4.23USD	capsule

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

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
US5317032	No	1994-05-31	2011-05-31
US6414016	No	2002-07-02	2020-09-05
US7064148	No	2006-06-20	2022-08-30
US7795312	No	2010-09-14	2024-09-17
US8071613	No	2011-12-06	2020-09-05
US8748481	No	2014-06-10	2025-09-01
US8088934	No	2012-01-03	2021-05-18
US8114890	No	2012-02-14	2020-09-05
US8026393	No	2011-09-27	2027-10-25
US6583174	No	2003-06-24	2020-10-16
US7417067	No	2008-08-26	2020-10-16
US8338639	No	2012-12-25	2027-01-23
US8097649	No	2012-01-17	2020-10-16
US8779187	No	2014-07-15	2027-01-23
US6982283	No	2006-01-03	2022-12-04
US8097653	No	2012-01-17	2022-11-14
US8389542	No	2013-03-05	2022-11-14

Properties

State

Solid

Experimental Properties

Property	Value	Source
water solubility	Practically insoluble	Not Available
logP	4.3	Not Available

Predicted Properties

Property	Value	Source
Water Solubility	0.0256 mg/mL	ALOGPS
logP	2.76	ALOGPS
logP	4.56	Chemaxon
logS	-4.2	ALOGPS
pKa (Strongest Acidic)	4.3	Chemaxon
pKa (Strongest Basic)	-4.4	Chemaxon
Physiological Charge	-1	Chemaxon
Hydrogen Acceptor Count	5	Chemaxon
Hydrogen Donor Count	2	Chemaxon
Polar Surface Area	83.83 Å2	Chemaxon
Rotatable Bond Count	11	Chemaxon
Refractivity	95.6 m3·mol-1	Chemaxon
Polarizability	42.35 Å3	Chemaxon
Number of Rings	2	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	+	0.9765
Blood Brain Barrier	+	0.8984
Caco-2 permeable	-	0.5526
P-glycoprotein substrate	Substrate	0.6672
P-glycoprotein inhibitor I	Non-inhibitor	0.9187
P-glycoprotein inhibitor II	Non-inhibitor	0.9255
Renal organic cation transporter	Non-inhibitor	0.9196
CYP450 2C9 substrate	Non-substrate	0.8359
CYP450 2D6 substrate	Non-substrate	0.8465
CYP450 3A4 substrate	Non-substrate	0.5319
CYP450 1A2 substrate	Non-inhibitor	0.8806
CYP450 2C9 inhibitor	Non-inhibitor	0.9088
CYP450 2D6 inhibitor	Non-inhibitor	0.9458
CYP450 2C19 inhibitor	Non-inhibitor	0.8776
CYP450 3A4 inhibitor	Non-inhibitor	0.7675
CYP450 inhibitory promiscuity	Low CYP Inhibitory Promiscuity	0.9821
Ames test	Non AMES toxic	0.6696
Carcinogenicity	Non-carcinogens	0.9454
Biodegradation	Not ready biodegradable	0.9939
Rat acute toxicity	3.2264 LD50, mol/kg	Not applicable
hERG inhibition (predictor I)	Weak inhibitor	0.9739
hERG inhibition (predictor II)	Non-inhibitor	0.8709

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 MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	splash10-0ab9-0009000000-5845a293e608c8fac14b
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	splash10-0uk9-0009000000-f999cce8bd58cd38e02c
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	splash10-0ab9-2129000000-6a6ab50456381df0e3c6
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	splash10-05fr-0291000000-2d3f690171a13efb37a2
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	splash10-056c-9620000000-4c63d8ffa1bf76fd4869
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	splash10-01ca-3089000000-5fd0023128e83c0370b1
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]-	191.05211	predicted	DeepCCS 1.0 (2019)
[M+H]+	193.5118	predicted	DeepCCS 1.0 (2019)
[M+Na]+	200.87692	predicted	DeepCCS 1.0 (2019)

Targets

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Details1. Chloride channel protein 2

Kind

Protein

Organism

Humans

Pharmacological action

Yes

Actions

Inducer

General Function

Voltage-gated chloride channel activity

Specific Function

Voltage-gated chloride channel. Chloride channels have several functions including the regulation of cell volume; membrane potential stabilization, signal transduction and transepithelial transport.

Gene Name

CLCN2

Uniprot ID

P51788

Uniprot Name

Chloride channel protein 2

Molecular Weight

98534.425 Da

References

1. Authors unspecified: Lubiprostone: RU 0211, SPI 0211. Drugs R D. 2005;6(4):245-8. [Article]
2. Moeser AJ, Nighot PK, Engelke KJ, Ueno R, Blikslager AT: Recovery of mucosal barrier function in ischemic porcine ileum and colon is stimulated by a novel agonist of the ClC-2 chloride channel, lubiprostone. Am J Physiol Gastrointest Liver Physiol. 2007 Feb;292(2):G647-56. Epub 2006 Oct 19. [Article]
3. Lacy BE, Levy LC: Lubiprostone: a chloride channel activator. J Clin Gastroenterol. 2007 Apr;41(4):345-51. [Article]
4. Crowell MD, Harris LA, DiBaise JK, Olden KW: Activation of type-2 chloride channels: a novel therapeutic target for the treatment of chronic constipation. Curr Opin Investig Drugs. 2007 Jan;8(1):66-70. [Article]
5. Lacy BE, Chey WD: Lubiprostone: chronic constipation and irritable bowel syndrome with constipation. Expert Opin Pharmacother. 2009 Jan;10(1):143-52. doi: 10.1517/14656560802631319 . [Article]
6. Ambizas EM, Ginzburg R: Lubiprostone: a chloride channel activator for treatment of chronic constipation. Ann Pharmacother. 2007 Jun;41(6):957-64. Epub 2007 May 22. [Article]
7. Lacy BE, Levy LC: Lubiprostone: a novel treatment for chronic constipation. Clin Interv Aging. 2008;3(2):357-64. [Article]
8. Johanson JF, Ueno R: Lubiprostone, a locally acting chloride channel activator, in adult patients with chronic constipation: a double-blind, placebo-controlled, dose-ranging study to evaluate efficacy and safety. Aliment Pharmacol Ther. 2007 Jun 1;25(11):1351-61. [Article]
9. Kapoor S: Emerging new therapeutic options for the management of opioid induced constipation. J Pain Palliat Care Pharmacother. 2010 Mar;24(1):98-9. doi: 10.3109/15360280903475593. [Article]
10. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]

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Drug created at June 13, 2005 13:24 / Updated at February 20, 2024 23:55