Lubiprostone targets chloride channel type 2 (ClC-2) in the apical membrane of gastrointestinal epithelial cells. Activation of ClC-2 leads to increased chloride secretion into the intestinal lumen, which is followed by passive movement of sodium and water, resulting in increased intestinal fluid volume. This enhances gastrointestinal motility and softens the stool, providing relief from constipation.

In vitro, lubiprostone activates ClC-2 chloride channels in gastrointestinal epithelial cells. The compound's activity can be measured using electrophysiological techniques such as patch-clamp or Ussing chamber assays to measure chloride ion flux. Lubiprostone shows selective activation of ClC-2 over other chloride channels, contributing to its gastrointestinal specificity.

In vivo, lubiprostone has demonstrated efficacy in animal models of constipation. The compound increases gastrointestinal transit and fecal output in rodent models. In clinical trials, lubiprostone has shown significant improvement in bowel movement frequency and stool consistency in patients with chronic idiopathic constipation and opioid-induced constipation. The compound is administered orally.

In vitro ClC-2 channel assays for lubiprostone are performed using cells expressing recombinant ClC-2 channels. The compound's ability to activate the channel is measured using electrophysiological techniques such as patch-clamp, or using fluorescent membrane potential or ion flux assays. EC₅₀ values for channel activation are determined from concentration-response curves.

In vitro cellular assays for lubiprostone are conducted in gastrointestinal epithelial cell lines expressing ClC-2. Cells are treated with various concentrations of lubiprostone, and chloride ion flux is measured using fluorescent chloride-sensitive probes or electrophysiological techniques. The compound's effects on cell viability and proliferation are also assessed.

In vivo efficacy studies for lubiprostone are conducted in rodent models of constipation, such as the loperamide-induced constipation model. The compound is administered orally at doses ranging from 0.1–10 mg/kg. Gastrointestinal transit is measured using a charcoal meal or other markers. Fecal output and stool consistency are monitored. The compound's ability to increase intestinal motility is evaluated.

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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Lubiprostone is administered orally and has low systemic bioavailability due to extensive first-pass metabolism. The compound is rapidly converted to its active metabolite, which acts locally in the gastrointestinal tract. The elimination half-life is short, supporting twice-daily dosing. The compound is minimally absorbed and does not accumulate in the body.

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 generally well-tolerated. Common adverse events include nausea, diarrhea, and abdominal pain. Serious adverse events are rare. The compound is contraindicated in patients with mechanical gastrointestinal obstruction. Preclinical toxicology studies have shown no significant toxicity at therapeutic doses.

[1]. Functional analysis and clinical significance of chloride channel 2 expression in esophageal squamous cell carcinoma. Annals of Surgical Oncology, 2021, 28: 5384-5397.

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 can enhance intestinal motility, thereby promoting fecal excretion and alleviating symptoms associated with chronic idiopathic constipation. Activation of ClC-2 chloride ion channels may promote the restoration of mucosal barrier function by restoring the intestinal tight junction protein complex. Patch-clamp studies using human cell lines have shown that most of the beneficial biological activities of lubiprostone and its metabolites are found only in the apical (luminal) portion of gastrointestinal epithelial cells.

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Lubiprostone (Amitiza®) is a prostaglandin E1 derivative used for the treatment of chronic idiopathic constipation and opioid-induced constipation. It activates ClC-2 chloride channels in the gastrointestinal tract, increasing intestinal fluid secretion and enhancing motility. The compound is administered orally and has low systemic bioavailability. This product is for research use only and is not intended for human therapeutic use.

C20H32F2O5

390.46

390.221

333963-40-9

157920

White to off-white solid powder

1.2±0.1 g/cm3

532.3±50.0 °C at 760 mmHg

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](CCCCCCC(=O)O)C(=O)C[C@H]2O1)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-[(2R,4aR,5R,7aR)-2-(1,1-difluoropentyl)-2-hydroxy-6-oxo-3,4,4a,5,7,7a-hexahydrocyclopenta[b]pyran-5-yl]heptanoic acid