Tegaserod (Zelmac), an aminoguanidine indole derivative of serotonin, is a selective partial agonist highly selective for 5-HT4 receptor with an affinity constant in the nanomolar range. Tegaserod does not cause adverse pharmacodynamic effects, is absorbed rapidly after oral administration and distributes widely into tissues. Pharmacokinetics of oral tegaserod are linear in the 2–12 mg dose range. After oral administration tegaserod is metabolized mainly pre-systemically; when absorbed, intact tegaserod is excreted as N-glucuronides mainly via the bile. No clinically relevant drug–drug interactions were identified. Tegaserod has proven safe in toxicity studies.
In pharmacodynamic studies, tegaserod stimulated the peristaltic reflex in vitro, increased canine intestinal and colonic motility and transit, reduced visceral afferent firing or sensation in response to distension in animals, and accelerated gastric, small bowel and colonic transit in healthy patients, and small bowel transit in patients with constipation-predominant irritable bowel syndrome.
Three large phase III randomized, double-blinded, and placebo-controlled trials were performed predominantly in females (≈ 85%) with constipation-predominant irritable bowel syndrome. Overall, phase III results support efficacy as assessed by the subject’s global assessment of relief with significant improvement in secondary endpoints such as abdominal pain, bowel frequency and consistency. Tegaserod was well-tolerated; the most frequent adverse event was transient diarrhoea.