Brands, Medical Use, Clinical Data
Brands / Synonyms
SDZ HTF 919; Tegaserod maleate; Tegaserod [Usan:Inn:Ban]; Zelmac; Zelnorm; Zelnorm
Provides relief from the symptoms of irritable bowel syndrome including chronic idiopathic constipation.
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.
Rapidly absorbed after oral administration, with an absolute bioavailability of approximately 10%.
Oral LD50 in rat is 2000 mg/kg.
Biotrnasformation / Drug 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.
Zelnorm® (tegaserod maleate) is contraindicated in those patients with:
• severe renal impairment
• moderate or severe hepatic impairment
• a history of bowel obstruction, symptomatic gallbladder disease, suspected sphincter of Oddi dysfunction,
or abdominal adhesions
• a known hypersensitivity to the drug or any of its excipients
In vitro drug-drug interaction data with tegaserod indicated no inhibition of the cytochrome P450
isoenzymes CYP2C8, CYP2C9, CYP2C19, CYP2E1 and CYP3A4, whereas inhibition of CYP1A2 and CYP2D6 could not be excluded.
However, in vivo, no clinically relevant drug-drug interactions have been observed with dextromethorphan (CYP2D6
prototype substrate), and theophylline (CYP1A2 prototype substrate). There was no effect on the pharmacokinetics of
digoxin, oral contraceptives, and warfarin. The main human metabolite of tegaserod hydrogen maleate,
5-methoxyindole-3-carboxylic acid glucuronide, did not inhibit the activity of any of the above cytochrome P450
isoenzymes in in vitro tests.
A pharmacokinetic interaction study demonstrated that co-administration of tegaserod and
dextromethorphan did not change the pharmacokinetics of either compound to a clinically relevant extent. Dose
adjustment of either drug is not necessary when tegaserod is combined with dextromethorphan. Therefore, tegaserod is
not expected to alter the pharmacokinetics of drugs metabolized by CYP2D6 (e.g., fluoxetine, omeprazole,
A pharmacokinetic interaction study demonstrated that co-administration of tegaserod and theophylline
did not affect the pharmacokinetics of theophylline. Dose adjustment of theophylline is not necessary when tegaserod
is co-administered. Therefore, tegaserod is not expected to alter the pharmacokinetics of drugs metabolized by CYP1A2
(e.g., estradiol, omeprazole).
A pharmacokinetic interaction study with digoxin demonstrated that concomitant administration of
tegaserod reduced peak plasma concentration and exposure of digoxin by approximately 15%. This reduction of
bioavailability is not considered clinically relevant. When tegaserod is co-administered with digoxin dose adjustment
is unlikely to be required.
A pharmacokinetic and pharmacodynamic interaction study with warfarin demonstrated no effect of
concomitant administration of tegaserod on warfarin pharmacokinetics and pharmacodynamics. Dose adjustment of
warfarin is not necessary when tegaserod is co-administered.
Co-administration of tegaserod did not affect the steady-state pharmacokinetics of ethinylestradiol
and reduced peak concentrations and exposure of levonorgestrel by 8%. Tegaserod is not expected to alter the risk of
ovulation in subjects taking oral contraceptives. No alteration in oral contraceptive medication is necessary when
tegaserod is co-administered.