Identification

Name
Lubiprostone
Accession Number
DB01046  (APRD01298)
Type
Small Molecule
Groups
Approved, Investigational
Description

Lubiprostone is a medication used in the management of idiopathic chronic constipation. It is a bicyclic fatty acid (prostaglandin E1 derivative) which acts by specifically activating ClC-2 chloride channels on the apical aspect of gastrointestinal epithelial cells, producing a chloride-rich fluid secretion. These secretions soften the stool, increase motility, and promote spontaneous bowel movements (SBM).

Structure
Thumb
Synonyms
Not Available
External IDs
RU-0211
Product Images
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
AmitizaCapsule, gelatin coated8 ug/1OralStat Rx USA2006-01-31Not applicableUs
AmitizaCapsule24 mcgOralSucampo Pharma Americas, LlcNot applicableNot applicableCanada
AmitizaCapsule, gelatin coated8 ug/1OralTakeda2006-01-31Not applicableUs64764 08020180913 8702 1ayy2nf
AmitizaCapsule, gelatin coated24 ug/1OralCarilion Materials Management2006-01-31Not applicableUs
AmitizaCapsule, gelatin coated8 ug/1OralPhysicians Total Care, Inc.2010-08-19Not applicableUs
AmitizaCapsule, gelatin coated24 ug/1Oralbryant ranch prepack2006-01-31Not applicableUs
AmitizaCapsule, gelatin coated24 ug/1OralLake Erie Medical Dba Quality Care Produts Llc2011-06-01Not applicableUs
AmitizaCapsule, gelatin coated24 ug/1OralPhysicians Total Care, Inc.2008-12-16Not applicableUs
AmitizaCapsule, gelatin coated24 ug/1OralTakeda2006-01-31Not applicableUs
AmitizaCapsule, gelatin coated8 ug/1OralAvera McKennan Hospital2015-04-062018-06-08Us
Categories
UNII
7662KG2R6K
CAS number
136790-76-6
Weight
Average: 390.468
Monoisotopic: 390.221780456
Chemical Formula
C20H32F2O5
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

Pharmacology

Indication

For the treatment of chronic idiopathic constipation in the adult population. Also used for the treatment of irritable bowel syndrome with constipation in women who are 18 years of age or older.

Associated Conditions
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.

TargetActionsOrganism
AChloride channel protein 2
inducer
Human
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
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%).

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AbacavirLubiprostone may decrease the excretion rate of Abacavir which could result in a higher serum level.
AcarboseAcarbose may decrease the excretion rate of Lubiprostone which could result in a higher serum level.
AceclofenacAceclofenac may decrease the excretion rate of Lubiprostone which could result in a higher serum level.
AcemetacinAcemetacin may decrease the excretion rate of Lubiprostone which could result in a higher serum level.
AcetaminophenAcetaminophen may decrease the excretion rate of Lubiprostone which could result in a higher serum level.
AcetazolamideThe risk or severity of adverse effects can be increased when Acetazolamide is combined with Lubiprostone.
Acetylsalicylic acidAcetylsalicylic acid may decrease the excretion rate of Lubiprostone which could result in a higher serum level.
AclidiniumThe therapeutic efficacy of Lubiprostone can be decreased when used in combination with Aclidinium.
AcrivastineLubiprostone may decrease the excretion rate of Acrivastine which could result in a higher serum level.
AcyclovirAcyclovir may decrease the excretion rate of Lubiprostone which could result in a higher serum level.
Food Interactions
Not Available

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. [PubMed:17263187]
  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 . [PubMed:19236188]
  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. [PubMed:17519292]
  4. Lacy BE, Levy LC: Lubiprostone: a novel treatment for chronic constipation. Clin Interv Aging. 2008;3(2):357-64. [PubMed:18686757]
External Links
KEGG Drug
D04790
KEGG Compound
C13707
PubChem Compound
157920
PubChem Substance
46505874
ChemSpider
138948
ChEMBL
CHEMBL1201134
Therapeutic Targets Database
DAP000208
PharmGKB
PA164777012
Drugs.com
Drugs.com Drug Page
Wikipedia
Lubiprostone
ATC Codes
A06AX03 — Lubiprostone
AHFS Codes
  • 56:92.00 — Miscellaneous GI Drugs
FDA label
Download (244 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedBasic ScienceIrritable Bowel Syndrome (IBS) / Other Constipation1
1CompletedTreatmentIrritable Bowel Syndrome (IBS)1
1Unknown StatusTreatmentChronic Constipation, Methanogenesis1
2Active Not RecruitingTreatmentHuman Immunodeficiency Virus (HIV)1
2TerminatedTreatmentIrritable Bowel Syndrome (IBS)1
2, 3CompletedTreatmentChronic Idiopathic Constipation1
2, 3CompletedTreatmentOccasional Constipation1
3Active Not RecruitingTreatmentHealthy Volunteers1
3CompletedDiagnosticCarcinoma, Colorectal1
3CompletedTreatmentChronic Idiopathic Constipation5
3CompletedTreatmentConstipation - Functional3
3CompletedTreatmentConstipation-predominant Irritable Bowel Syndrome (IBS-C)1
3CompletedTreatmentIrritable Bowel Syndrome (IBS) / Occasional Constipation1
3CompletedTreatmentOccasional Constipation3
3CompletedTreatmentOpioid Induced Bowel Dysfunction4
4CompletedDiagnosticInflammatory Bowel Diseases (IBD)1
4CompletedHealth Services ResearchChronic Idiopathic Constipation1
4CompletedTreatmentColonoscopy2
4CompletedTreatmentDiabetes Mellitus (DM) / Occasional Constipation1
4CompletedTreatmentDisseminated Sclerosis / Occasional Constipation1
4CompletedTreatmentHealthy Volunteers1
4CompletedTreatmentOccasional Constipation2
4CompletedTreatmentParkinson's Disease (PD)1
4Unknown StatusTreatmentOccasional Constipation1
Not AvailableCompletedNot AvailableAdults / Irritable Bowel Syndrome (IBS) / Occasional Constipation1
Not AvailableCompletedBasic ScienceConstipation-predominant Irritable Bowel Syndrome (IBS-C)1
Not AvailableCompletedTreatmentBowel Preparation for Colonoscopy1
Not AvailableCompletedTreatmentCystic Fibrosis (CF) / Occasional Constipation1
Not AvailableCompletedTreatmentOccasional Constipation1
Not AvailableNot Yet RecruitingNot AvailableOpioid Induced Constipation (OIC)1
Not AvailableTerminatedDiagnosticDiabetes, Diabetes Mellitus Type 1 / Type 2 Diabetes Mellitus1
Not AvailableTerminatedTreatmentOccasional Constipation / Parkinson's Disease (PD)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
  • Catalent Pharma Solutions
  • Stat Rx Usa
  • Takeda Pharmaceutical Co. Ltd.
Dosage forms
FormRouteStrength
CapsuleOral24 mcg
Capsule, gelatin coatedOral24 ug/1
Capsule, gelatin coatedOral8 ug/1
Prices
Unit descriptionCostUnit
Amitiza 8 mcg capsule4.27USD capsule
Amitiza 24 mcg capsule4.23USD capsule
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US5317032No1994-05-312011-05-31Us
US6414016No2002-07-022020-09-05Us
US7064148No2006-06-202022-08-30Us
US7795312No2010-09-142024-09-17Us
US8071613No2011-12-062020-09-05Us
US8748481No2014-06-102025-09-01Us
US8088934No2012-01-032021-05-18Us
US8114890No2012-02-142020-09-05Us
US8026393No2011-09-272027-10-25Us
US6583174No2003-06-242020-10-16Us
US7417067No2008-08-262020-10-16Us
US8338639No2012-12-252027-01-23Us
US8097649No2012-01-172020-10-16Us
US8779187No2014-07-152027-01-23Us
US6982283No2006-01-032022-12-04Us
US8097653No2012-01-172022-11-14Us
US8389542No2013-03-052022-11-14Us

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubilityPractically insolubleNot Available
logP4.3Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0256 mg/mLALOGPS
logP2.76ALOGPS
logP4.56ChemAxon
logS-4.2ALOGPS
pKa (Strongest Acidic)4.3ChemAxon
pKa (Strongest Basic)-4.4ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area83.83 Å2ChemAxon
Rotatable Bond Count11ChemAxon
Refractivity95.6 m3·mol-1ChemAxon
Polarizability42.35 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9765
Blood Brain Barrier+0.8984
Caco-2 permeable-0.5526
P-glycoprotein substrateSubstrate0.6672
P-glycoprotein inhibitor INon-inhibitor0.9187
P-glycoprotein inhibitor IINon-inhibitor0.9255
Renal organic cation transporterNon-inhibitor0.9196
CYP450 2C9 substrateNon-substrate0.8359
CYP450 2D6 substrateNon-substrate0.8465
CYP450 3A4 substrateNon-substrate0.5319
CYP450 1A2 substrateNon-inhibitor0.8806
CYP450 2C9 inhibitorNon-inhibitor0.9088
CYP450 2D6 inhibitorNon-inhibitor0.9458
CYP450 2C19 inhibitorNon-inhibitor0.8776
CYP450 3A4 inhibitorNon-inhibitor0.7675
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9821
Ames testNon AMES toxic0.6696
CarcinogenicityNon-carcinogens0.9454
BiodegradationNot ready biodegradable0.9939
Rat acute toxicity3.2264 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9739
hERG inhibition (predictor II)Non-inhibitor0.8709
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 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

Taxonomy

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
show 5 more
Substituents
Prostaglandin skeleton / Medium-chain fatty acid / Halogenated fatty acid / Heterocyclic fatty acid / Hydroxy fatty acid / Oxane / Fatty acid / Fluorohydrin / Halohydrin / Hemiacetal
show 17 more
Molecular Framework
Aliphatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
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. [PubMed:15991886]
  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. [PubMed:17053162]
  3. Lacy BE, Levy LC: Lubiprostone: a chloride channel activator. J Clin Gastroenterol. 2007 Apr;41(4):345-51. [PubMed:17413599]
  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. [PubMed:17263187]
  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 . [PubMed:19236188]
  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. [PubMed:17519292]
  7. Lacy BE, Levy LC: Lubiprostone: a novel treatment for chronic constipation. Clin Interv Aging. 2008;3(2):357-64. [PubMed:18686757]
  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. [PubMed:17509103]
  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. [PubMed:20345211]
  10. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Prostaglandin-e2 9-reductase activity
Specific Function
NADPH-dependent reductase with broad substrate specificity. Catalyzes the reduction of a wide variety of carbonyl compounds including quinones, prostaglandins, menadione, plus various xenobiotics. ...
Gene Name
CBR1
Uniprot ID
P16152
Uniprot Name
Carbonyl reductase [NADPH] 1
Molecular Weight
30374.73 Da
References
  1. 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 . [PubMed:19236188]
  2. Lacy BE, Levy LC: Lubiprostone: a novel treatment for chronic constipation. Clin Interv Aging. 2008;3(2):357-64. [PubMed:18686757]

Drug created on June 13, 2005 07:24 / Updated on November 20, 2018 00:50