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

aimTo investigate the in vivo effect of treatment with tolterodine on debrisoquine 4-hydroxylation (an index of CYP2D6 activity), omeprazole 5-hydroxylation (CYP2C19), omeprazole sulphoxidation (CYP3A4) and caffeine N3-demethylation (CYP1A2).

methodsTwelve healthy male volunteers (eight extensive metabolisers [EMs] and four poor metabolisers [PMs] with respect to CYP2D6) received 4 mg tolterodine L-tartrate orally twice daily for 6 days. All subjects were EMs with respect to CYP2C19. The subjects received single oral doses of debrisoquine (10 mg), omeprazole (20 mg) and caffeine (100 mg) for determination of the appropriate metabolic ratios (MR). The drugs were given on separate consecutive days, before, during and after the co-administration of tolterodine.

resultsMean 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 quantifiable in PMs. The mean MR of debrisoquine (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 mean MR of omeprazole hydroxylation and sulphoxidation or caffeine metabolism were not changed in the presence of tolterodine in either EMs or PMs. Debrisoquine 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.

conclusionsTolterodine, administered at twice the expected therapeutic dosage, did not change the disposition of the probe drugs debrisoquine, omeprazole and caffeine and thus had no detectable effect on the activities of CYPs 2D6, 2C19, 3A4 and 1A2. Alteration of the metabolism of substrates of these enzymes by tolterodine is unlikely to occur.