Fluoxetine inhibits the metabolism of tolterodine—pharmacokinetic implications and proposed clinical relevance

Aims To investigate the change in disposition of tolterodine during coadministration of the potent cytochrome P450 2D6 (CYP2D6) inhibitor fluoxetine. Methods Thirteen patients received tolterodine l‐tartrate 2 mg twice daily for 2.5 days, followed by fluoxetine 20 mg once daily for 3 weeks and then concomitant administration for an additional 2.5 days. They were characterized as extensive metabolizers (EM1 with one functional CYP2D6 gene, EM2 with two functional genes) or poor metabolizers (PM). Results Nine patients, three EM2 and four EM1 and two PM, completed the trial. Following tolterodine administration, the area under the serum concentration–time curve (AUC) of tolterodine was 4.4‐times and 30‐times higher among EM1 and PM, respectively, compared with EM2. The AUC of the 5‐hydroxymethyl metabolite (5‐HM) was not quantifiable in PM. Fluoxetine significantly decreased (P