Fluoxetine inhibits the metabolism of tolterodine-pharmacokinetic implications and proposed clinical relevance.
OBJECTIVE
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<0.002) the oral clearance of tolterodine by 93% in EM2 and by 80% in EM1. The AUC of 5-HM increased in EM2 and decreased in EM1. However, the exposure to the active moiety (unbound tolterodine +5-HM) was not significantly increased in the two phenotypes. The subdivision of the EM group showed a 2.1-fold increase in active moiety in EM2 but the exposure was still similar to EM1 compared with before the interaction.


CONCLUSIONS
The study suggests a difference in the pharmacokinetics of tolterodine and its 5-hydroxymethyl metabolite depending on the number of functional CYP2D6 genes. Fluoxetine significantly inhibited the hydroxylation of tolterodine. Despite the effect on the pharmacokinetics of tolterodine in extensive metabolizers, the clinical effect is expected to be within normal variation.
Brynne
N
N
Department of Clinical Pharmacology, Pharmacia & Upjohn AB, SE-112 87 Stockham, Sweden. niclas.brynne@eu.pnu.com
Svanström
C
C
Aberg-Wistedt
A
A
Hallén
B
B
Bertilsson
L
L
D001559:Benzhydryl Compounds / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics; D003408:Cresols / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics; D018592:Cross-Over Studies; D019389:Cytochrome P-450 CYP2D6 / Q000172:deficiency / Q000235:genetics; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D005473:Fluoxetine / Q000494:pharmacology*; D006801:Humans; D006900:Hydroxylation; D008875:Middle Aged; D018727:Muscarinic Antagonists / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics; D010352:Patient Dropouts; D010641:Phenotype; D010665:Phenylpropanolamine; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D013997:Time Factors; D000068737:Tolterodine Tartrate
D001559:Benzhydryl Compounds; D003408:Cresols; D019389:Cytochrome P-450 CYP2D6; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D005473:Fluoxetine; D018727:Muscarinic Antagonists; D010665:Phenylpropanolamine; D017367:Selective Serotonin Reuptake Inhibitors; D000068737:Tolterodine Tartrate