In vitro metabolism of tegaserod in human liver and intestine: Assessment of drug interactions

Tegaserod is a selective 5-HT4 receptor partial agonist with promotile acti vity 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 inv estigate the effect of tegaserod on CYP-catalyzed reactions involving other compounds. Tegaserod was metabolized in human liver microsomes to O-desmet hyl tegaserod at a low rate. This metabolite was also formed by cDNA expres sed CYP2D6, and the reaction in human liver microsomes was inhibited by qui nidine. 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 tegaser od to the N-glucuronides, suggesting a contribution of the small intestine to the presystemic metabolism. 5-Methoxyindale-3-carboxylic acid (M29.0), t he main metabolite in human plasma, was generated in vitro by a sequence of reactions starting with nonenzymatic acid-catalyzed hydrolysis, followed b y enzymatic oxidation and conjugation with glucuronic acid. Tegaserod inhib ited CYP2C8, CYP2C9, CYP2C19, CYP2E1, and CYP3A only to a small extent with IC50 values >30 muM. Tegaserod more effectively inhibited CYP1A2 and CYP2D 6 with K-i values of 0.84 and 0.85 muM, respectively. However, these K-i va lues are approximately 140-fold greater than the maximal tegaserod plasma c oncentrations following the clinically relevant 6-mg oral dose given to hea lthy volunteers. M29.0, the main circulating metabolite, did not demonstrat e any inhibitory potential toward cytochrome P450 enzymes in vitro. Therefo re, clinically relevant metabolic drug interactions with tegaserod seem unl ikely.