Vol. 29, Issue 10, 1269-1276, October 2001

In Vitro Metabolism of Tegaserod in Human Liver and Intestine: Assessment of Drug Interactions

Alison E. M. Vickers, Markus Zollinger, Robert Dannecker, Ronald Tynes, Francis Heitz, and Volker Fischer

Preclinical Safety, Novartis Institute for Biomedical Research, East Hanover, New Jersey (A.E.M.V., V.F.); and Novartis Pharma AG, Basel, Switzerland (M.Z., R.D., R.T., F.H.)

Tegaserod is a selective 5-HT₄ receptor partial agonist with promotile activity in the gastrointestinal tract. This study was designed to describe the metabolic pathways of tegaserod in the human liver and small intestine in vitro, to identify the enzymes involved in tegaserod metabolism, and to investigate the effect of tegaserod on CYP-catalyzed reactions involving other compounds. Tegaserod was metabolized in human liver microsomes to O-desmethyl tegaserod at a low rate. This metabolite was also formed by cDNA expressed CYP2D6, and the reaction in human liver microsomes was inhibited by quinidine. In human liver slices, direct N-glucuronidation of tegaserod at the guanidine nitrogens (M43.2, M43.8, and M45.3) was found, with M43.8 being the major metabolite. Human small intestine slices also metabolized tegaserod to the N-glucuronides, suggesting a contribution of the small intestine to the presystemic metabolism. 5-Methoxyindole-3-carboxylic acid (M29.0), the main metabolite in human plasma, was generated in vitro by a sequence of reactions starting with nonenzymatic acid-catalyzed hydrolysis, followed by enzymatic oxidation and conjugation with glucuronic acid. Tegaserod inhibited CYP2C8, CYP2C9, CYP2C19, CYP2E1, and CYP3A only to a small extent with IC₅₀ values >30 µM. Tegaserod more effectively inhibited CYP1A2 and CYP2D6 with K_i values of 0.84 and 0.85 µM, respectively. However, these K_i values are approximately 140-fold greater than the maximal tegaserod plasma concentrations following the clinically relevant 6-mg oral dose given to healthy volunteers. M29.0, the main circulating metabolite, did not demonstrate any inhibitory potential toward cytochrome P450 enzymes in vitro. Therefore, clinically relevant metabolic drug interactions with tegaserod seem unlikely.