BIOTRANSFORMATION OF TOLTERODINE, A NEW MUSCARINIC RECEPTOR ANTAGONIST, IN MICE, RATS, AND DOGS

Tolterodine is a new muscarinic receptor antagonist intended for the t reatment of urinary urge incontinence and other symptoms associated wi th an overactive bladder. The in vivo metabolism of C-14-labeled tolte rodine was investigated in rats, mice, and dogs by analysis of blood a nd urine samples, whereas in vitro metabolism studies were performed b y incubation of [C-14]tolterodine with mouse, rat, dog, and human live r microsomes in the presence of NADPH. Tolterodine was extensively met abolized in vivo. Mice and dogs showed similar metabolite patterns, wh ich correlated well with that observed in humans. In these species, to lterodine 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 aldehy de, the 5-carboxylic acid metabolite. The other pathway involved dealk ylation of the nitrogen, In the subsequent phase II metabolism, tolter odine and the metabolites were conjugated with glucuronic acid to vari ous degrees. Rats exhibited more extensive metabolism and a markedly d ifferent metabolite pattern, with metabolites also being formed by hyd roxylation of the unsubstituted benzene ring. In addition, a gender di fference was observed, with male rats showing more extensive metabolis m than females. Incubation of [C-14]tolterodine with liver microsomes yielded a total of five metabolites with rat liver microsomes and thre e with mouse, dog, and human liver microsomes, The 5-hydroxymethyl met abolite of tolterodine and N-dealkylated tolterodine were major metabo lites in all incubations, representing 83-99% of total metabolism. Alt hough the extent of metabolism varied among species, the metabolic pro files were similar. However, rat liver microsomes also formed metaboli tes hydroxylated in the unsubstituted benzene ring. These results show that the metabolism of tolterodine in mice and dogs corresponds to th at observed in humans, whereas rats exhibit a different metabolite pat tern.