PHARMACOKINETICS AND PHARMACODYNAMICS OF TOLTERODINE IN MAN - A NEW DRUG FOR THE TREATMENT OF URINARY-BLADDER OVERACTIVITY

The aim of this study was to determine the pharmacokinetics, pharmacod ynamics, and safety of tolterodine following single oral and intraveno us doses in healthy volunteers. A secondary aim was to identify major urinary metabolites and determine mass balance. Single oral doses of 0 .2, 0.4, 0.8, 1.6, 3.2, 6.4, and 12.5 mg of tolterodine (as the tartra te salt) were given to 17 healthy male volunteers. Two intravenous dos es (0.64 and 1.28 mg) were administered to 8 of the volunteers and mas s balance was studied after a single oral dose of 5 mg (C-14)-tolterod ine in 6 subjects. Tolterodine was rapidly absorbed following oral adm inistration (time to peak serum concentration 0.9 +/- 0.4 h). The abso lute bioavailability was highly variable, ranging from 10 to 70%. The volume of distribution at steady-state ranged from 0.9 to 1.6 l/kg and systemic clearance ranged from 0.23 to 0.52 l/h/kg, which resulted in a terminal half-life of 2 - 3 h. Tolterodine exhibited high first-pas s metabolism and 2 hepatic metabolic pathways were identified: oxidati on and dealkylation. Independent of route of administration, < 1% of t he parent compound was excreted unchanged in urine. Five metabolites w ere structurally identified in urine. Following oral administration of (C-14)-tolterodine, the excretion of radioactivity into urine and fec es was 77 +/- 4.0% and 17 +/- 3.5%, respectively. Tolterodine decrease d stimulated salivation after 3.2 mg, increased heart rate after 6.4 m g, and nearpoint of vision after 12.8 mg. Six of 8 subjects reported m icturition difficulties after a dose of 12.8 mg. The lack of a direct relationship between tolterodine serum concentrations and effects on s timulated salivation suggested the presence of pharmacologically activ e metabolite(s).