From the Guidelines
Lubiprostone activates the CIC-2 chloride channel, not CFTR, and is used to treat constipation by promoting intestinal fluid secretion. Chloride channels play crucial roles in cellular ion transport and fluid secretion. CFTR (Cystic Fibrosis Transmembrane conductance Regulator) is a chloride channel primarily found in epithelial cells that regulates salt and water movement across cell membranes. The chloride-bicarbonate exchanger (also called anion exchanger) swaps chloride for bicarbonate ions across membranes, helping regulate intracellular pH and chloride concentration. NKCC1 (Na⁺-K⁺-2Cl⁻ cotransporter) is located on the basolateral membrane of secretory epithelia and transports sodium, potassium, and two chloride ions into the cell simultaneously, providing chloride for secretion through apical chloride channels like CFTR.
According to the most recent guideline, the American Gastroenterological Association recommends using lubiprostone in patients with chronic idiopathic constipation 1. This recommendation is based on the results of three 4-week randomized double-blinded placebo-controlled trials that evaluated the use of lubiprostone for the management of CIC. The studied dose of lubiprostone was 24μg twice daily, and studies were conducted in the United States and Japan.
Key points to consider:
- Lubiprostone is a chloride channel activator, resulting in increased intestinal fluid and accelerated GI transit 1.
- The AGA suggests using lubiprostone in patients with IBS-C, with a dosage of 8 mg twice daily for women 1.
- Lubiprostone is also approved for the treatment of CIC in men and women at a dosage of 24 mg twice daily 1.
- Dysfunction in chloride channels, particularly CFTR, leads to diseases like cystic fibrosis, characterized by thick mucus secretions and impaired fluid transport.
From the FDA Drug Label
Lubiprostone is a locally acting chloride channel activator that enhances a chloride-rich intestinal fluid secretion without altering sodium and potassium concentrations in the serum. Lubiprostone acts by specifically activating ClC-2, which is a normal constituent of the apical membrane of the human intestine, in a protein kinase A–independent fashion
Although the text does mention ClC-2, it does not mention CFTR, chloride bicarbonate exchanger, or NK2CL on the basolateral membrane.
The FDA drug label does not answer the question.
From the Research
Chloride Channels and Lubiprostone
- Lubiprostone activates type 2 chloride channels (ClC-2) in the apical membrane of intestinal epithelial cells, stimulating chloride secretion and inducing peristalsis and laxation 2, 3, 4, 5, 6
- The activation of ClC-2 channels by lubiprostone increases chloride and fluid secretion into the intestines, resulting in relief of constipation 4, 6
Mechanism of Action
- Lubiprostone acts locally within the intestinal tract and is rapidly metabolized, with very low systemic bioavailability 3, 4
- It increases gastrointestinal fluid secretion in a dose-dependent manner, as demonstrated in animal studies 3
Clinical Efficacy
- Lubiprostone has been shown to be effective in the treatment of chronic idiopathic constipation and irritable bowel syndrome with constipation (IBS-C) 2, 3, 4, 6
- It improves stool frequency, consistency, and symptoms of straining and incomplete evacuation, with a good safety profile 2, 3, 4, 6
Specific Chloride Channels and Transporters
- CFTR (cystic fibrosis transmembrane conductance regulator) is a chloride channel that is dysfunctional or absent in cystic fibrosis, leading to viscous secretions and constipation 5
- Lubiprostone may be especially effective for constipation in patients with cystic fibrosis because it utilizes an alternate chloride channel (ClC-2) 5
- There is no direct information available on the effect of lubiprostone on the chloride bicarbonate exchanger or NK2CL on the basolateral membrane in the provided studies