Tolterodine, a new muscarinic receptor antagonist, is metabolized by cytochromes P450 2D6 and 3A in human liver microsomes. Drug Metab Dispos 26:289–293

This paper is available online at http://www.dmd.org ABSTRACT: 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 enzymes involved in the metabolic pathway, tolterodine was incubated with microsomes from 10 different human liver samples where various cytochrome P450 activities had been rank ordered. Strong correlation was found between the formation of the 5-hydroxymethyl metabolite of tolterodine (5-HM) and CYP2D6 activity (r 2 , 0.87), as well as between the formation of N-dealkylated tolterodine and CYP3A activity (r 2 , 0.97). When tolterodine was incubated with human liver microsomes in the presence of compounds known to interact with different P450 isoforms, quinidine was found to be the strongest inhibitor of the formation of 5-HM. Ketoconazole and troleandomycin were found to be the strongest inhibitors of the formation of N-dealkylated tolterodine. A weak inhibitory effect on the formation of N-dealkylated tolterodine was found with sulfaphenazole, 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 expressing CYP2C9, -2C19, and -3A4. The K m for formation of N-dealkylated tolterodine by CYP3A4 was similar to that obtained in human liver microsomes and higher for CYP2C9 and -2C19. We conclude from these studies that the formation of 5-HM is catalyzed by CYP2D6 and that the formation of N-dealkylated tolterodine is predominantly catalyzed by CYP3A isoenzymes in human liver microsomes. Tolterodine [(R)-N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-phenylpropanamine] is a new muscarinic receptor antagonist specifically developed for the treatment of urinary urge incontinence and other symptoms associated with overactive bladder In a previous study in healthy volunteers, one subject showed notably lower systemic clearance than the overall average. This dissimilarity was probably due to differences in metabolic capacit