Vol. 26, Issue 6, 528-535, June 1998

Biotransformation of Tolterodine, a New Muscarinic Receptor Antagonist, in Mice, Rats, and Dogs

Stig H. G. Andersson, Anders Lindgren, and Hans Postlind

Department of Drug Metabolism, Pharmacia & Upjohn AB

Tolterodine is a new muscarinic receptor antagonist intended for the treatment of urinary urge incontinence and other symptoms associated with an overactive bladder. The in vivo metabolism of ¹⁴C-labeled tolterodine was investigated in rats, mice, and dogs by analysis of blood and urine samples, whereas in vitro metabolism studies were performed by incubation of [¹⁴C]tolterodine with mouse, rat, dog, and human liver microsomes in the presence of NADPH. Tolterodine was extensively metabolized in vivo. Mice and dogs showed similar metabolite patterns, which correlated well with that observed in humans. In these species, tolterodine was metabolized along two different pathways, with the more important being the stepwise oxidation of the 5-methyl group to yield the 5-hydroxymethyl metabolite of tolterodine and then, via the aldehyde, the 5-carboxylic acid metabolite. The other pathway involved dealkylation of the nitrogen. In the subsequent phase II metabolism, tolterodine and the metabolites were conjugated with glucuronic acid to various degrees. Rats exhibited more extensive metabolism and a markedly different metabolite pattern, with metabolites also being formed by hydroxylation of the unsubstituted benzene ring. In addition, a gender difference was observed, with male rats showing more extensive metabolism than females. Incubation of [¹⁴C]tolterodine with liver microsomes yielded a total of five metabolites with rat liver microsomes and three with mouse, dog, and human liver microsomes. The 5-hydroxymethyl metabolite of tolterodine and N-dealkylated tolterodine were major metabolites in all incubations, representing 83-99% of total metabolism. Although the extent of metabolism varied among species, the metabolic profiles were similar. However, rat liver microsomes also formed metabolites hydroxylated in the unsubstituted benzene ring. These results show that the metabolism of tolterodine in mice and dogs corresponds to that observed in humans, whereas rats exhibit a different metabolite pattern.