化合物信息

Drug Groups

approved; investigational

Description

Lubiprostone is a medication used in the management of idiopathic chronic constipation. It is a bicyclic fatty acid (prostaglandin E1 derivative) which acts by specifically activating ClC-2 chloride channels on the apical aspect of gastrointestinal epithelial cells, producing a chloride-rich fluid secretion. These secretions soften the stool, increase motility, and promote spontaneous bowel movements (SBM).

Indication

For the treatment of chronic idiopathic constipation in the adult population. Also used for the treatment of irritable bowel syndrome with constipation in women who are 18 years of age or older.

Pharmacology

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.

Toxicity

In a definitive Phase 1 cardiac repolarization study, 51 patients were administered a single oral dose of 144 mcg of lubiprostone, which is 6 times the normal single administration dose. Thirty-nine (39) of the 51 patients experienced an adverse event. The adverse events reported in >1% of this group included the following: nausea (45.1%), vomiting (27.5%), diarrhea (25.5%), dizziness (17.6%), loose or watery stools (13.7%), headache (11.8%), retching (7.8%), abdominal pain (5.9%), flushing or hot flush (5.9%), dyspnea (3.9%), pallor (3.9%), stomach discomfort (3.9%), syncope (3.9%), upper abdominal pain (2.0%), anorexia (2.0%), asthenia (2.0%), chest discomfort (2.0%), dry mouth (2.0%), hyperhidrosis (2.0%), skin irritation (2.0%) and vasovagal episode (2.0%).

Affected Organisms

Biotransformation

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.

Absorption

Lubiprostone has low systemic availability following oral administration and concentrations of lubiprostone in plasma are below the level of quantitation (10 pg/mL).

Half Life

0.9 to 1.4 hours

Protein Binding

94%

Elimination

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.

References

External Links