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Identification
NameLubiprostone
Accession NumberDB01046  (APRD01298)
TypeSmall Molecule
GroupsApproved, 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
SynonymsNot Available
External Identifiers
  • RU-0211
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Amitizacapsule24 mcgoralSucampo Pharma Americas LlcNot applicableNot applicableCanada
Amitizacapsule, gelatin coated8 ug/1oralSTAT Rx USA LLC2006-01-31Not applicableUs
Amitizacapsule, gelatin coated8 ug/1oralAvera Mc Kennan Hospital2015-04-06Not applicableUs
Amitizacapsule, gelatin coated24 ug/1oralCarilion Materials Management2006-01-31Not applicableUs
Amitizacapsule, gelatin coated24 ug/1oralTakeda Pharmaceuticals America, Inc.2006-01-31Not applicableUs
Amitizacapsule, gelatin coated8 ug/1oralTakeda Pharmaceuticals America, Inc.2006-01-31Not applicableUs
Amitizacapsule, gelatin coated8 ug/1oralPhysicians Total Care, Inc.2010-08-19Not applicableUs
Amitizacapsule, gelatin coated24 ug/1oralPhysicians Total Care, Inc.2008-12-16Not applicableUs
Amitizacapsule, gelatin coated24 ug/1oralLake Erie Medical DBA Quality Care Products LLC2011-06-01Not applicableUs
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International BrandsNot Available
Brand mixturesNot Available
SaltsNot Available
Categories
UNII7662KG2R6K
CAS number136790-76-6
WeightAverage: 390.468
Monoisotopic: 390.221780456
Chemical FormulaC20H32F2O5
InChI KeyWGFOBBZOWHGYQH-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)[[email protected]](CCCCCCC(O)=O)[C@@]1([H])CC[C@@](O)(O2)C(F)(F)CCCC
Taxonomy
DescriptionThis 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.
KingdomOrganic compounds
Super ClassLipids and lipid-like molecules
ClassFatty Acyls
Sub ClassEicosanoids
Direct ParentProstaglandins and related compounds
Alternative Parents
Substituents
  • Prostaglandin skeleton
  • Medium-chain fatty acid
  • Halogenated fatty acid
  • Heterocyclic fatty acid
  • Hydroxy fatty acid
  • Oxane
  • Fatty acid
  • Fluorohydrin
  • Halohydrin
  • Hemiacetal
  • Ketone
  • Cyclic ketone
  • Monocarboxylic acid or derivatives
  • Carboxylic acid
  • Oxacycle
  • Organoheterocyclic compound
  • Carboxylic acid derivative
  • Organohalogen compound
  • Carbonyl group
  • Hydrocarbon derivative
  • Organic oxide
  • Alkyl halide
  • Alkyl fluoride
  • Organic oxygen compound
  • Organofluoride
  • Organooxygen compound
  • Aliphatic heteropolycyclic compound
Molecular FrameworkAliphatic heteropolycyclic compounds
External DescriptorsNot Available
Pharmacology
IndicationFor 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.
PharmacodynamicsChronic 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 actionLubiprostone 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.
Related Articles
AbsorptionLubiprostone has low systemic availability following oral administration and concentrations of lubiprostone in plasma are below the level of quantitation (10 pg/mL).
Volume of distributionNot Available
Protein binding94%
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 eliminationPeak 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 life0.9 to 1.4 hours
ClearanceNot Available
ToxicityIn 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
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
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 )
Pharmacoeconomics
ManufacturersNot Available
Packagers
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)
US5317032 No1994-05-312011-05-31Us
US6414016 No2000-09-052020-09-05Us
US6583174 No2000-10-162020-10-16Us
US6982283 No2002-12-042022-12-04Us
US7064148 No2002-08-302022-08-30Us
US7417067 No2000-10-162020-10-16Us
US7795312 No2004-09-172024-09-17Us
US8026393 No2007-10-252027-10-25Us
US8071613 No2000-09-052020-09-05Us
US8088934 No2001-05-182021-05-18Us
US8097649 No2000-10-162020-10-16Us
US8097653 No2002-11-142022-11-14Us
US8114890 No2000-09-052020-09-05Us
US8338639 No2007-01-232027-01-23Us
US8389542 No2002-11-142022-11-14Us
US8748481 No2005-09-012025-09-01Us
US8779187 No2007-01-232027-01-23Us
Properties
StateSolid
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 RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot 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
ATC CodesA06AX03
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelDownload (244 KB)
MSDSNot Available
Interactions
Drug Interactions
Drug
MethadoneThe therapeutic efficacy of Lubiprostone can be decreased when used in combination with Methadone.
Food InteractionsNot 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
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. Catalyzes the reduction of the antitumor anthracyclines doxorubicin and daunorubicin to the cardiotoxic compounds doxorubicinol and daunorubicinol. Can convert prostaglandin E2 to prostaglandin F2-alp...
Gene Name:
CBR1
Uniprot ID:
P16152
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 ]
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Drug created on June 13, 2005 07:24 / Updated on June 29, 2016 01:50