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Lubiprostone (formerly SPI-0211; RU-0211; RU0211; Spi0211; trade name Amitiza), a bicyclic fatty acid derived from prostaglandin E1 that acts as potent activator of ClC-2 chloride channels, is an FDA-approved drug to manage idiopathic chronic constipation. It was approved by the U.S. FDA in 2006 for the treatment of chronic idiopathic constipation, predominantly irritable bowel syndrome-associated constipation in women and opioid-induced constipation.
Physicochemical Properties
| Molecular Formula | C20H32F2O5 |
| Molecular Weight | 390.46 |
| Exact Mass | 390.221 |
| CAS # | 136790-76-6 |
| Related CAS # | Lubiprostone-d7;1217675-13-2 |
| PubChem CID | 157920 |
| Appearance | White to off-white solid powder |
| Density | 1.2±0.1 g/cm3 |
| Boiling Point | 532.3±50.0 °C at 760 mmHg |
| Melting Point | 56-59ºC |
| Flash Point | 275.7±30.1 °C |
| Vapour Pressure | 0.0±3.2 mmHg at 25°C |
| Index of Refraction | 1.486 |
| LogP | 2.85 |
| Hydrogen Bond Donor Count | 2 |
| Hydrogen Bond Acceptor Count | 7 |
| Rotatable Bond Count | 11 |
| Heavy Atom Count | 27 |
| Complexity | 525 |
| Defined Atom Stereocenter Count | 4 |
| SMILES | CCCCC([C@]1(CC[C@H]2[C@H](O1)CC(=O)[C@@H]2CCCCCCC(=O)O)O)(F)F |
| InChi Key | WGFOBBZOWHGYQH-MXHNKVEKSA-N |
| InChi Code | 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 |
| Chemical Name | 7-[(1R,3R,6R,7R)-3-(1,1-Difluoropentyl)-3-hydroxy-8-oxo-2-oxabicyclo[4.3.0]non-7-yl]heptanoic acid |
| Synonyms | RU 0211; Spi-0211; RU-0211; Spi 0211; RU 0211; RU0211; Spi0211; Lubiprostone hemiketal; Lubiprostone. trade name Amitiza. |
| HS Tariff Code | 2934.99.9001 |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| ln Vitro |
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| ln Vivo |
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| Animal Protocol |
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| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion Lubiprostone has low systemic availability following oral administration and concentrations of lubiprostone in plasma are below the level of quantitation (10 pg/mL). 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. Metabolism / Metabolites 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. Biological Half-Life 0.9 to 1.4 hours |
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| Toxicity/Toxicokinetics |
Hepatotoxicity In clinical trials, lubiprostone therapy was not associated with significant changes in serum enzyme levels or episodes of clinically apparent liver injury. Since its approval and marketing, isolated case reports of serum aminotransferase elevations have been reported to the sponsor, but there have been no published reports of clinically apparent liver injury attributable to lubiprostone. Thus, liver injury from lubiprostone must be extremely rare, if it occurs at all. Likelihood score: E (unlikely cause of clinically apparent liver injury). Effects During Pregnancy and Lactation ◉ Summary of Use during Lactation No information is available on the use of lubiprostone during breastfeeding. The manufacturer reports that the drug and its metabolite are undetectable in rat milk and would not be expected to cause any adverse effects in a breastfed infant. Monitor the breastfed infant for diarrhea. ◉ Effects in Breastfed Infants Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk Relevant published information was not found as of the revision date. Protein Binding 94% |
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| References | Br J Pharmacol.2008 May;154(1):126-35;Gastroenterology.2009 Sep;137(3):976-85. | ||
| Additional Infomation |
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). Lubiprostone is a Chloride Channel Activator. The mechanism of action of lubiprostone is as a Chloride Channel Activator. Lubiprostone is an activator of chloride channels (ClC-2) in the intestine and is used for treatment of chronic constipation and irritable bowel syndrome. Lubiprostone has not been linked to serum enzyme elevations during treatment or to episodes of clinically apparent liver injury. Lubiprostone is a bicyclic fatty acid derived from prostaglandin E1 and a chloride channel activator with laxative activity. Upon intake, lubiprostone specifically binds to and activates the type 2 chloride channel (ClC-2) in the apical membrane of the gastrointestinal epithelium. This produces an efflux of chloride ions, thereby drawing water into the gastrointestinal lumen. The resulting increased amounts of intestinal fluid soften the stool, increase motility, and improve bowel movements. Member of a bicyclic fatty acid class of compounds derived from PROSTAGLANDIN E1 involved in chloride channel gating. Drug 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. It is also indicated for the treatment of irritable bowel syndrome with constipation (IBS-C) in female patients ≥18 years old. Treatment of constipation 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. 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. |
Solubility Data
| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 3.25 mg/mL (8.32 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 32.5 mg/mL clear DMSO stock solution to 400 μL of PEG300 and mix evenly; then add 50 μL of Tween-80 to the above solution and mix evenly; then add 450 μL of normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 3.25 mg/mL (8.32 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 32.5 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 3: ≥ 3.25 mg/mL (8.32 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 32.5 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.5611 mL | 12.8054 mL | 25.6108 mL | |
| 5 mM | 0.5122 mL | 2.5611 mL | 5.1222 mL | |
| 10 mM | 0.2561 mL | 1.2805 mL | 2.5611 mL |