Ketoconazole inhibits the metabolism of tolterodine in subjects with deficient CYP2D6 activity

Br J Clin Pharmacol. 1999 Oct;48(4):564-72. doi: 10.1046/j.1365-2125.1999.00053.x.


Aims: To investigate the pharmacokinetics and safety of tolterodine and tolterodine metabolites after single-and multiple-dose administration in the absence and presence of ketoconazole, an inhibitor of cytochrome P450 (CYP) 3A4, in healthy volunteers with deficient CYP2D6 activity, i.e. poor metabolisers of debrisoquine.

Methods: Eight healthy volunteers received single oral doses (2 mg) of tolterodine l-tartrate. Following a wash-out period of about 3 months, six of the subjects participated in a multiple-dose (1 mg twice daily) phase of the study. Ketoconazole 200 mg was given once daily for 4-4.5 days during both the single and multiple dose tolterodine administration phases. Blood samples were drawn and the pharmacokinetics of tolterodine and its metabolites were determined.

Results: A decrease (P<0.01) in apparent oral clearance of tolterodine, from 10- 12 l h-1 to 4.3-4.7 l h-1, was obtained during concomitant administration of ketoconazole, yielding at least a two-fold increase in the area under the serum concentration-time curve after single as well as after multiple doses following single dose administration of tolterodine. The mean (+/-s.d.) terminal half-life increased by 50% from 9.7+/-2.7 h to 15+/-5.4 h in the presence of ketoconazole.

Conclusions: CYP3A4 is the major enzyme involved in the elimination of tolterodine in individuals with deficient CYP2D6 activity (poor metabolisers), since oral clearance of tolterodine decreased by 60% during ketoconazole coadministration. This inhibition resulted in 2.1-fold increase in AUC.

Publication types

  • Clinical Trial
  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antifungal Agents / pharmacology*
  • Benzhydryl Compounds / administration & dosage
  • Benzhydryl Compounds / adverse effects
  • Benzhydryl Compounds / blood
  • Benzhydryl Compounds / metabolism*
  • Cresols / administration & dosage
  • Cresols / adverse effects
  • Cresols / blood
  • Cresols / metabolism*
  • Cross-Over Studies
  • Cytochrome P-450 CYP2D6 / deficiency*
  • Cytochrome P-450 CYP2D6 / genetics
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme Inhibitors
  • Drug Interactions
  • Female
  • Humans
  • Ketoconazole / pharmacology*
  • Male
  • Mixed Function Oxygenases / antagonists & inhibitors
  • Muscarinic Antagonists / administration & dosage
  • Muscarinic Antagonists / adverse effects
  • Muscarinic Antagonists / blood
  • Muscarinic Antagonists / metabolism*
  • Phenotype
  • Phenylpropanolamine*
  • Time Factors
  • Tolterodine Tartrate


  • Antifungal Agents
  • Benzhydryl Compounds
  • Cresols
  • Cytochrome P-450 Enzyme Inhibitors
  • Muscarinic Antagonists
  • Phenylpropanolamine
  • Tolterodine Tartrate
  • Mixed Function Oxygenases
  • CYP3A protein, human
  • Cytochrome P-450 CYP2D6
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • Ketoconazole