INFLUENCE OF CYP2D6 POLYMORPHISM ON THE PHARMACOKINETICS AND PHARMACODYNAMICS OF TOLTERODINE

Objective: To determine whether cytochrome P450 2D6 (CYP2D6) is involv ed in the metabolism of tolterodine by investigating potential differe nces in pharmacokinetics and pharmacodynamics (heart rate, accommodati on, and salivation) of tolterodine and its Ei-hydroxymethyl metabolite between poor metabolizers and extensive metabolizers of debrisoquin ( INN, debrisoquine). Methods: Sixteen male subjects (eight extensive me tabolizers and eight poor metabolizers) received 4 mg tolterodine by m outh twice a day for 8 days followed by a single intravenous infusion of 1.8 mg tolterodine for 30 minutes after a washout period, Doses wer e given as the tartrate salt, The pharmacokinetics of tolterodine and Ei-hydroxymethyl metabolite were determined, and the pharmacodynamics were measured, Results: The mean systemic clearance of tolterodine was significantly lower (p < 0.001) among poor metabolizers (9.0 +/- 2.1 L/hr) compared with extensive metabolizers (44 +/- 13 L/hr), resulting in a fourfold longer elimination half-life (p < 0.001), The terminal half-life of the 5-hydroxymethyl metabolite (2.9 +/- 0.4 hours) was sl ightly longer than that of the parent compound (2.3 +/- 0.6 hours) amo ng extensive metabolizers. but the 5-hydroxymethyl metabolite was unde tectable in the serum of poor metabolizers. Only minor differences in pharmacodynamic effects after tolterodine dosage were observed between the groups. Tolterodine caused a similar decrease in salivation in bo th panels. The decrease occurred when the concentration of unbound tol terodine and 5-hydroxymethyl metabolite among extensive metabolizers w as comparable with that of tolterodine among poor metabolizers, Conclu sions: Tolterodine is extensively metabolized by CYP2D6 with high spec ificity. Despite the effect on pharmacokinetics, the CYP2D6 polymorphi sm does not appear to be of great importance in the antimuscarinic eff ect, probably because of the additive action of parent drug and active metabolite.