136790-76-6

Hazard Information

Chemical Properties

Lubiprostone is a white, odorless crystals or crystalline powder and is very soluble in ether and ethanol, and practically insoluble in hexane and water. It is an activator of ClC-2 chloride channels, used in the management of idiopathic chronic constipation.

Uses

Lubiprostone is a bicyclic fatty acid metabolite analog of Prostaglandin E1. It activates specific chloride channels in the gastrointestinal tract to stimulate intestinal fluid secretion, increase gastrointestinal transit, and improve symptoms of constipation.

Application

Lubiprostone is a locally acting chloride channel activator for the treatment of gastrointestinal disorders.

Biochem/physiol Actions

Lubiprostone is a bicyclic fatty acid that activates ClC-2 and CFTR chloride channels. Some reports suggest that lubiprostone opens CFTR or both CFTR and ClC-2 through interactions with the prostaglandin receptor EP4. Lubiprostone is used clinically to treat idiopathic chronic constipation and irritible bowel syndrome.

Synthesis

1236109-40-2

136790-76-6

The general procedure for the synthesis of 7-((1R,2R,3R)-2-(4,4-difluoro-3-oxooctyl)-3-hydroxy-5-oxocyclopentyl)heptenoic acid from the compound (CAS: 1236109-40-2) was as follows: the (Z)-7-[(1R,2R,3R)-2-((E)-4,4-difluoro-3-oxo-1-enyl)-3-( phenylmethoxy)-5-oxocyclopentyl]-5-heptenoic acid (10, where R1 is phenyl, R2 and R3 are hydrogens, R6 is a hydrogen, and the bond between the 9b and 9b2 positions is a double bond) was dissolved in ethyl acetate (5 mL) and 10% palladium carbon (5 mg) was added. The suspension was hydrogenated at atmospheric pressure for 10 hours. Upon completion of the reaction, the mixture was filtered through Celite. The crude product was recrystallized from ethyl acetate/heptane to give Lubiprostone as a crystalline material in 70% yield. High Resolution Mass Spectrometry (ESI+) [M + NH4]+ Molecular Formula: C20H36F2NO5: Calculated value m/z: 408.25561 amu, measured value: 408.25626 amu.

in vivo

Lubiprostone (0.1-0.5 mg/kg, po, once daily for 5 weeks) ameliorates high fat diet (HFD)-induced non-alcoholic fatty liver disease (NAFLD) in mouse models^[2].
Lubiprostone (0.01-1 mg/kg, po, singe dose) reduces Indomethacin (HY-14397)-induced small intestinal damage and prevents enterobacterial invasion in rats models^[3].

Animal Model:	HFD-induced C57BL/6 NAFLD mouse model[2]
Dosage:	0.1-0.5 mg/kg
Administration:	po, once daily for 5 weeks
Result:	Reduced liver weight, plasma liver injury markers, hepatic bacterial load, improved intestinal permeability, and increased portal high density lipoprotein (HDL) cholesterol levels.

Animal Model:	Indomethacin (HY-14397)-induced small intestinal damage in Sprague-Dawley rats models[3]
Dosage:	0.01-1 mg/kg
Administration:	po, singe dose
Result:	Reduced small intestinal damage.

Questions And Answer

• General Description

  Lubiprostone (brand name: Amitiza) is a drug that is prescribed as a treatment for acute idiopathic constipation that is associated with bloating, stomach pain and straining in bowel movements. The drug is prescribed in cases where a patient is experiencing infrequent bowel movements that may persist for about 3 months or a longer period of time without necessarily being resultant of certain medications or diseases. The drug may also be used to relieve constipation that may result from specific opioid (narcotic) use amongst people who have persistent pain that is not caused by cancer. Lubiprostone is classified as a laxative and its mechanism of action entails enhancing the flow of fluid into the bowel for easier bowel movements. ;

• Pharmacology

  Marketed under the trade name Amitiza, Lubiprostone is a chloride channel activator which is mainly used for the treatment of idiopathic (due to an unknown cause) chronic constipation, predominantly irritable bowel syndrome-associated constipation in women and opioid-induced constipation. Lubiprostone is an oral medication approved by the FDA in January 2006.
  The mechanism of action of lubiprostone is the same as chloride channel activator. It functions by binding and activating ClC-2 chloride channels in the apical membrane of the gastrointestinal epithelium, which produces an efflux of chloride-rich fluid secretion. The increased amounts of secretions are effective to soften the stool, increase motility, promote spontaneous bowel movements (SBM), and speed up transit of stool in the colon. Therefore, the relevant symptoms, such as abdominal pain and bloating, can be reduced. ;

• Indication

  Lubiprostone is indicated for the treatment of acute idiopathic constipation in adult patients. It is also used as a medication for irritable bowel syndrome which is accompanied by constipation in women who are over 18 years. ;

• Contraindication

  The drug is contraindicated in patients with an established hypersensitivity to Lubiprostone or any of its metabolites. Lubiprostone may result in mild or severe effects on a developing fetus hence the use of the medication is not recommended during pregnancy.
  The drug should not be administered to patients experiencing severe diarrhoea or vomiting as it may increase their chances of hypotension and syncope. Lubiprostone is also contraindicated in patients who have a history of GI obstruction, GI disease, gastric cancer, cholelithiasis, inflammatory bowel disease, faecal impaction, diverticulitis, Crohn’s disease, and abdominal pain. ;

• Mechanism of Action

  Lubiprostone activates CIC-2 chloride pathways, which is a primary component of the apical membrane in human intestines, specifically in a protein Kinase A unrestrained action. The activation of CIC-2 pathways results in an overflow of chloride ions into the lumen, which also results in an overflow of sodium ions through a paracellular channel to establish isoelectric neutrality. Subsequently, water facilitates the movement of sodium into the lumen to sustain an isotonic equilibrium, which increases the secretion of intestinal fluids. Lubiprostone enhances movability in the intestines once the intestinal fluids have been secreted, which in turn allows for easy passage of stool and a reduction in the symptoms that are closely-linked with acute idiopathic constipation. Stimulation of the CIC-2 chloride pathways may also trigger the functionality of the mucosal barrier by replacing solid protein complexes in the intestine. Studies in patch clamp cells in humans indicate that a significant portion of favourable biological activity of the drug and its metabolites takes place in the luminal (apical) section of the gastrointestinal epithelium. ;

• Information on Dosing

  A Lubiprostone capsule comes in 8mcg and 24mcg, where the recommended dosage in adults with acute constipation is 24mcg to be taken twice per day orally. For adults experiencing Irritable bowel syndrome, 8mcg of Lubiprostone should be administered twice per day orally in women who are above 18 years.
  For patients with opioid-induced constipation or acute idiopathic constipation, the initial dosage for liver dysfunction ranges from 9mcg-16mcg administered orally twice per day. If the initial dose is tolerated in the body but there are no significant responses within the recommended interval, the dose should be increased while monitoring the response of the patient to Lubiprostone. ;

• Drug Interactions

  Diphenylheptane opioids such as methadone have been highlighted in non-clinical studies to minimize the activation of CIC-2 depending on the Lubiprostone doses present in the gastrointestinal tract.
  The efficiency of Lubiprostone may be reduced if the patient is on concurrent treatment with diphenylheptane opioids, herbal medications, vitamins and other over-the-counter medications, hence the need to notify the healthcare provider on other medications in use before the administration of Lubiprostone. ;

• Lubiprostone Warnings

  Patients with suggestive symptoms for GI obstruction should undergo a thorough examination to ascertain the absence of an obstruction before Lubiprostone is administered for therapeutic purposes. The probability of chronic dyspnea which is indicated through difficulties in breathing and chest tightness 30-60 minutes after the initial administration of the drug, which suggests that the patient should contact their healthcare provider.
  Lubiprostone is not recommended for patients with severe diarrhoea as it may result in additional nausea and diarrhoea. For patients taking two daily doses of 24mcg of Lubiprostone, there are increased chances of hypotension and syncope which may necessitate hospitalization. ;

• Side Effects

  Some of the common side effects associated with Lubiprostone include exhaustion, chest discomfort, selling on the lower legs, ankles, feet or hands, dizziness, headaches, heartburn, vomiting, gas, bloating or stomach pain and nausea.
  Severe side effects associated with Lubiprostone include throat tightness, skin rash, swelling on the throat, tongue, lips or mouth, lightheadedness, fainting, chest tightness, difficulties in breathing, and severe diarrhoea.
  1-10% of the patients on Lubiprostone indicate that they experienced fatigue, dry mouth, dyspepsia, dyspnea, loose stools, flatulence, abdominal distension, and abdominal discomfort. A majority of these side effects may disappear but if they persist one should discontinue Lubiprostone and contact their healthcare provider immediately. ;

• References

  https://en.wikipedia.org/wiki/Lubiprostone
  http://www.medicinenet.com/lubiprostone/article.htm
  https://www.drugbank.ca/drugs/DB01046
  https://pubchem.ncbi.nlm.nih.gov/compound/157920#section=Top;

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