Tolterodine does not affect the human in vivo metabolism of the probe drugs caffeine, debrisoquine and omeprazole

Aim To investigate the in vivo effect of treatment with tolterodine on debr isoquine 4-hydroxylation (an index of CYP2D6 activity), omeprazole 5-hydrox ylation (CYP2C19), omeprazole sulphoxidation (CYP3A4) and caffeine N-3-deme thylation (CYP1A2). Methods Twelve healthy male volunteers (eight extensive metabolisers [EMs] and four poor metabolisers [PMs] with respect to CYP2D6) received 4 mg tolt erodine L-tartrate orally twice daily for 6 days. AU subjects were EMs with respect to CYP2C19. The subjects received single oral doses of debrisoquin e (10 mg), omeprazole (20 mg) and caffeine (100 mg) for determination of th e appropriate metabolic ratios (MR). The drugs were given on separate conse cutive days, before, during and after the co-administration of tolterodine. Results Mean serum tolterodine concentrations were 5-10 times higher in PMs than in EMs. Serum concentrations of the active 5-hydroxymethyl metabolite of tolterodine, 5-HM, were not quantifrable in PMs. The mean MR of debriso quine (95% confidence interval) during tolterodine treatment was 0.50 (0.25 -0.99) and did not differ statistically from the values before [0.49 (0.20- 1.2)] and after tolterodine administration [0.46 (0.14-1.6)] in EMs. The me an MR of omeprazole hydroxylation and sulphoxidation or caffeine metabolism were not changed in the presence of tolterodine in either EMs or PMs. Debr isoquine and caffeine had no significant effect on the AUC(1,3 h) of either tolterodine or 5-HM, but during omeprazole administration small decreases (13-19%) in these parameters were seen. Conclusions Tolterodine, administered at twice the expected therapeutic dos age, did not change the disposition of the probe drugs debrisoquine, omepra zole and caffeine and thus had no detectable effect on the activities of CY Ps 2D6, 2C19, 3A4 and 1A2. Alteration of the metabolism of substrates of th ese enzymes by tolterodine is unlikely to occur.