EP1 receptor (activation mediates contraction of stomach longitudinal muscle)
EP4 receptor (activation mediates inhibition of neuronally mediated contractions of colon circular muscle) [1]

Lubiprostone induces a robust secretory response in T84 monolayers. Lubiprostone induces a rise in cAMP levels that was sensitive to EP(4)-receptor blockage in T84 cells. Lubiprostone induces a contraction in rat and human stomach longitudinal muscle, which is inhibited by pretreatment with the EP(1) receptor antagonist but not by the EP(3) or EP(4) receptor antagonists. Lubiprostone also reduces electrically stimulated, neuronal contractions in rat and human colon circular muscle preparations. Lubiprostone (1 mM) stimulates higher elevations in TER despite lower I(sc) responses compared with the nonselective secretory agonist PGE(2) (1 mM).

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Cell Assay: Lubiprostone significantly reduces mucosal-to-serosal fluxes of (3)H-labeled mannitol to levels comparable to those of normal control tissues and restored occludin localization to tight junctions. Lubiprostone causes comparable and maximal increases of I(sc) in T84 cells. Lubiprostone-induced increases in iodide efflux are ~80% of those obtained with forskolin. Lubiprostone activates Cl(-) secretion in T84 cells via cAMP, protein kinase A, and by increasing apical membrane CFTR protein. Lubiprostone, applied to the small intestinal mucosa in eight concentrations ranging from 1-3000 nM, evokes increases in Isc in a concentration-dependent manner with an EC50 of 42.5 nM. Lubiprostone applied to the mucosa of the colon in eight concentrations ranging from 1-3000 nM evokes increases in Isc in a concentration-dependent manner with an EC50 of 31.7 nM.

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In rat forestomach longitudinal muscle, Lubiprostone (3 nM - 10 µM) induced a concentration-dependent contraction with pEC50 of 7.0±0.0 (n=4) and maximal effect of 95±3% of the response to 1 µM PGE2. The contraction was unaffected by TTX (1 µM) or scopolamine (10 µM), indicating direct muscle contraction. The EP1 receptor antagonist EP1A (300 nM) rightward-shifted the curve (pEC50 reduced to 6.2±0.2, apparent pKB 7.6, n=6), while EP3 (L-798106, 1 µM) or EP4 (GW627368X, 1 µM) antagonists had no effect. [1]
In rat forestomach circular muscle, Lubiprostone induced contraction (1 µM produced 62±13% of PGE2 response, n=8; pEC50 not calculable). EP1 antagonist reduced this effect (1 µM lubiprostone contraction 22±10% of PGE2), while EP3/EP4 antagonists had no effect. Butaprost (EP2 agonist, 1 µM) had no effect on basal tone, but 10 µM induced small relaxation. [1]
In rat colon longitudinal muscle, Lubiprostone (10 nM - 10 µM) caused contraction (max at 10 µM: 140±74% of 1 µM PGE2 response, n=4). The EP1 antagonist (1 µM) tended to reduce this (to 58±25% at 10 µM, not significant), while EP3/EP4 antagonists had no effect. Butaprost (10 µM) induced large relaxation. [1]
In rat colon circular muscle, Lubiprostone had little effect on baseline tension. On electrically field stimulated (EFS) neuronally mediated contractions (2.5 Hz for stomach, 5 Hz for colon; 0.5 ms pulses, 10 s every 1 min), Lubiprostone caused inhibition with pIC50 of 8.9±0.4 and maximal inhibition of 67±3% (n=7). This effect was unchanged by EP1 (EP1A 1 µM, pIC50 8.2±0.5) or EP3 (L-798106 1 µM, pIC50 8.4±0.1) antagonists, but was reduced by EP4 antagonist (GW627368X 1 µM, pIC50 6.7±1.1, n=7). Butaprost (up to 1 mM) had no effect; 10 µM butaprost inhibited EFS contractions but this was not blocked by AH6809. Lubiprostone (10 nM) had no effect on carbachol (1 µM)-induced contractions. [1]
In human proximal stomach longitudinal muscle, Lubiprostone induced concentration-dependent contraction with pEC50 of 6.4±0.2 and maximal effect at 10 µM of 102±17% of 1 µM PGE2 response (n=3). EP1 antagonist (EP1A 1 µM) rightward-shifted the curve (pEC50 reduced to 6.1±0.7) and depressed maximal response (10 µM lubiprostone reduced to 44±27% of PGE2). EP3 or EP4 antagonists had no effect. [1]
In human colon circular muscle, Lubiprostone had little effect on baseline tension. On EFS-induced contractions (5 Hz), Lubiprostone caused inhibition with pIC50 of 8.7±0.9 and maximal effect at 10 µM reducing amplitude to 37±8% of control (n=6). EP1 (EP1A 1 µM, pIC50 8.6±0.6) and EP3 (L-798106 1 µM, pIC50 8.6±0.5) antagonists had no effect, while EP4 antagonist (GW627368X 1 µM) tended to antagonize (pIC50 reduced to 7.7±0.4, P=0.39). [1]
In human colon longitudinal muscle, Lubiprostone had little effect on baseline tension but potentiated EFS-evoked contractions with pEC50 of 6.1±0.9 and maximum potentiation at 10 µM of 361±110% (n=6). This excitatory effect was reduced by EP1, EP3, or EP4 antagonists (1 µM each) – 10 µM lubiprostone potentiation reduced to 132±33%, 186±66%, and 175±55%, respectively. [1]

Lubiprostone induces a CdCl(2)-insensitive secretory response in mouse intestine, but fail to induce intestinal Cl(-) secretion in Cftr-null mice.

Absorption, Distribution and Excretion
Following oral administration of lubiprostone, its systemic bioavailability is low, with plasma concentrations below the limit of quantitation (10 pg/mL). Peak plasma concentrations occur at approximately 1.14 hours, and most of the drug is excreted in the urine within 48 hours. Lubiprostone and M3 are present only in trace amounts in human feces. Metabolism/Metabolites Human and animal studies have shown that lubiprostone is rapidly and extensively metabolized via 15-position reduction, α-chain β-oxidation, and ω-chain ω-oxidation. These biotransformations are not mediated by the hepatic cytochrome P450 system but appear to be mediated by universally expressed carbonyl reductases. M3, a metabolite of lubiprostone in humans and animals, is formed by the reduction of the carbonyl group at the 15-hydroxyl group and contains α-hydroxy and β-hydroxy epimers. M3 accounts for less than 10% of the radiolabeled lubiprostone dose.

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Biological half-life
0.9 to 1.4 hours

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Hepatotoxicity
In clinical trials, lubiprost treatment was not associated with significant changes in serum enzyme levels or clinically significant liver injury events. Since its approval, the sponsor has received some case reports of elevated serum transaminases, but there have been no published reports of clinically significant liver injury caused by lubiprost. Therefore, liver injury caused by lubiprost, even if it occurs, is extremely rare. Probability score: E (unlikely to cause clinically significant liver injury). Pregnancy and Lactation Effects ◉ Overview of Use During Lactation There is currently no information regarding the use of lubiprost during lactation. The manufacturer reports that the drug and its metabolites are undetectable in rat milk and are not expected to have any adverse effects on breastfed infants. Monitor breastfed infants for diarrhea. ◉ Effects on Breastfed Infants As of the revision date, no relevant published information was found.
◉ Effects on lactation and breast milk
As of the revision date, no relevant published information was found.

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Protein binding
94%

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Lubiprostone is a drug that remains mostly within the lumen of the gut before excretion in the faeces. It is derived from prostaglandin E1 and is indicated for the treatment of constipation. The nausea associated with Lubiprostone treatment (31% of patients) may be due to small intestinal distension following enhanced secretion or possibly due to activation of EP receptors on vagus nerve endings projecting into the mucosa. Lubiprostone may delay gastric emptying and accelerate overall colonic transit without accelerating ascending colon emptying, suggesting a direct motor effect in the distal colon in addition to its secretory effects. [1]

Br J Pharmacol.2008 May;154(1):126-35;Gastroenterology.2009 Sep;137(3):976-85.

Lubiprostone is a medication used to treat idiopathic chronic constipation. Lubiprostone is a derivative of prostaglandin E1, belonging to the bicyclic fatty acid family, and activates ClC-2 chloride ion channels located at the apical membrane of gastrointestinal epithelial cells. Activation of these channels promotes the secretion of chloride-rich fluids, thereby softening stool, increasing gastrointestinal motility, and inducing spontaneous defecation (SBM). Lubiprostone is a chloride channel activator. Its mechanism of action is as a chloride channel activator. Lubiprostone is an activator of intestinal chloride channels (ClC-2) and is used to treat chronic constipation and irritable bowel syndrome. No elevated serum enzymes or clinically significant liver injury events have been observed during treatment with lubiprostone. Lubiprostone is a bicyclic fatty acid derived from prostaglandin E1 and is a chloride channel activator with laxative activity. After administration, lubiprostone specifically binds to and activates type II chloride channels (ClC-2) on the apical membrane of gastrointestinal epithelial cells. This leads to chloride ion efflux, thereby drawing water into the gastrointestinal lumen. The resulting increase in intestinal fluid volume softens stool, increases intestinal motility, and improves defecation. It belongs to the bicyclic fatty acid class of compounds derived from prostaglandin E1 and participates in the gating of chloride ion channels. Drug Indications Lubiprostone is indicated for the treatment of chronic idiopathic constipation in adults, or for the treatment of opioid-induced constipation in patients with chronic non-cancerous pain. It is also indicated for the treatment of constipation-predominant irritable bowel syndrome (IBS-C) in women aged 18 years and older. Treatment of Constipation Mechanism of Action Lubiprostone exerts its effect by specifically activating the ClC-2 chloride ion channel, a normal component of the human intestinal apical membrane, and its action is independent of protein kinase A. Activation of the ClC-2 chloride ion channel leads to chloride ion efflux into the intestinal lumen, which in turn causes sodium ion efflux via the paracellular pathway to maintain isoelectric point balance. Therefore, water ions follow sodium ions into the intestinal lumen to maintain isotonic balance, thereby increasing intestinal fluid secretion. By increasing intestinal fluid secretion, lubiprostone enhances intestinal motility, thereby promoting fecal excretion and relieving symptoms associated with chronic idiopathic constipation. Activation of ClC-2 chloride channels may stimulate the restoration of mucosal barrier function by restoring the intestinal tight junction protein complex. Patch-clamp cell studies using human cell lines have shown that most of the beneficial bioactivity of lubiprostone and its metabolites is found only on the apical (luminal) portion of the gastrointestinal epithelium. Chronic idiopathic constipation is generally defined as infrequent or difficult bowel movements. Signs and symptoms associated with chronic idiopathic constipation (e.g., abdominal pain or discomfort, bloating, straining during defecation, and hard or lumpy stools) may be due to abnormal colonic motility, which delays the passage of intestinal contents and hinders the expulsion of rectal contents. One approach to treating chronic idiopathic constipation is to promote the secretion of intraperitoneal fluid by activating chloride channels on the apical membrane of gastrointestinal epithelial cells. Lubiprostone is a locally acting chloride channel activator that increases the secretion of chloride ions and fluids in the intestine without altering serum sodium and potassium concentrations.

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C20H32F2O5

390.46

390.221

C, 61.52; H, 8.26; F, 9.73; O, 20.49

136790-76-6

Lubiprostone-d7;1217675-13-2

157920

White to off-white solid powder

1.2±0.1 g/cm3

532.3±50.0 °C at 760 mmHg

56-59ºC

275.7±30.1 °C

0.0±3.2 mmHg at 25°C

1.486

2.85

2

7

11

27

525

4

CCCCC([C@]1(CC[C@H]2[C@H](O1)CC(=O)[C@@H]2CCCCCCC(=O)O)O)(F)F

WGFOBBZOWHGYQH-MXHNKVEKSA-N

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

7-[(1R,3R,6R,7R)-3-(1,1-Difluoropentyl)-3-hydroxy-8-oxo-2-oxabicyclo[4.3.0]non-7-yl]heptanoic acid

RU 0211; Spi-0211; RU-0211; Spi 0211; RU 0211; RU0211; Spi0211; Lubiprostone hemiketal; Lubiprostone. trade name Amitiza.

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

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.

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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.

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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.

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 (Please use freshly prepared in vivo formulations for optimal results.)