TOLTERODINE, A NEW MUSCARINIC RECEPTOR ANTAGONIST, IS METABOLIZED BY CYTOCHROMES P450 2D6 AND 3A IN HUMAN LIVER-MICROSOMES

Tolterodine, a new muscarinic receptor antagonist, is metabolized via two pathways: oxidation of the 5-methyl group and dealkylation of the nitrogen, In an attempt to identify the specific cytochrome P450 enzym es involved in the metabolic pathway, tolterodine was incubated with m icrosomes from 10 different human liver samples where various cytochro me P450 activities had been rank ordered. Strong correlation was found between the formation of the 5-hydroxymethyl metabolite of tolterodin e (5-HM) and CYP2D6 activity (r(2), 0.87), as well as between the form ation of N-dealkylated tolterodine and CYP3A activity (r(2), 0.97). Wh en tolterodine was incubated with human liver microsomes in the presen ce of compounds known to interact with different P450 isoforms, quinid ine was found to be the strongest inhibitor of the formation of 5-HM, Ketoconazole and troleandomycin were found to be the strongest inhibit ors of the formation of N-dealkylated tolterodine. A weak inhibitory e ffect on the formation of N-dealkylated tolterodine was found with sul faphenazole, whereas tranylcypromine did not inhibit the formation of this metabolite, Microsomes from cells overexpressing CYP2D6 formed 5- HM, whereas N-dealkylated tolterodine was formed by microsomes express ing CYP2C9, -2C19, and -3A4, The K-m for formation of N-dealkylated to lterodine by CYP3A4 was similar to that obtained in human liver micros omes and higher for CYP2C9 and -2C19. We conclude from these studies t hat the formation of 5-HM is catalyzed by CYP2D6 and that the formatio n of N-dealkylated tolterodine is predominantly catalyzed by CYP3A iso enzymes in human liver microsomes.