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.

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.

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%).

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

route of 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.