| Indication |
Provides relief from the symptoms of irritable bowel syndrome including chronic idiopathic constipation. |
| Pharmacodynamics |
Tegaserod is indicated for the short-term treatment of women
with irritable bowel syndrome (IBS) whose primary bowel symptom is
constipation. Irritable bowel syndrome with constipation and chronic
idiopathic constipation are both lower gastrointestinal dysmotility
disorders. Clinical investigations have shown that both motor and
sensory functions of the gut appear to be altered in patients suffering
from irritable bowel syndrome (IBS), while in patients with chronic
idiopathic constipation, reduced intestinal motility is the predominant
cause of the condition. Both the enteric nervous system, which acts to
integrate and process information in the gut, and 5-hydroxytryptamine
(5-HT, serotonin) are thought to represent key elements in the etiology
of both IBS and idiopathic constipation. Approximately 95% of serotonin
is found throughout the gastrointestinal tract, primarily stored in
enterochromaffin cells but also in enteric nerves acting as a
neurotransmitter. Serotonin has been shown to be involved in regulating
motility, visceral sensitivity and intestinal secretion. Investigations
suggest an important role of serotonin Type-4 (5-HT4) receptors in the maintenance of gastrointestinal functions in humans. 5-HT4 receptor mRNA has been found throughout the human gastrointestinal tract. |
| Mechanism of action |
Tegaserod is a 5-HT4 receptor partial agonist that binds with high affinity at human 5-HT4 receptors, whereas it has no appreciable affinity for 5-HT3 or dopamine receptors. It has moderate affinity for 5-HT1 receptors. Tegaserod, by acting as an agonist at neuronal 5-HT4
receptors, triggers the release of further neurotransmitters such as
calcitonin gene-related peptide from sensory neurons. The activation of
5-HT4 receptors in the gastrointestinal tract stimulates the
peristaltic reflex and intestinal secretion, as well as inhibits
visceral sensitivity. |
| Absorption |
Rapidly absorbed after oral administration, with an absolute bioavailability of approximately 10%. |
| Volume of distribution |
|
| Protein binding |
98% |
| Metabolism |
Tegaserod is metabolized mainly via two pathways. The first is a
presystemic acid catalyzed hydrolysis in the stomach followed by
oxidation and conjugation which produces the main metabolite of
tegaserod, 5-methoxyindole-3-carboxylic acid glucuronide. The main
metabolite has negligible affinity for 5-HT4 receptors in
vitro. The second metabolic pathway of tegaserod is direct
glucuronidation which leads to generation of three isomeric
N-glucuronides. |
| Route of elimination |
Approximately two-thirds of the orally administered dose of
tegaserod is excreted unchanged in the feces, with the remaining
one-third excreted in the urine, primarily as the main metabolite. |
| Half life |
11 ± 5 hours |
| Clearance |
- 77 +/- 15 L/h [IV administration]
|
| Toxicity |
Oral LD50 in rat is 2000 mg/kg. |
