Effects of strong CYP2D6 and 3A4 inhibitors, paroxetine and ketoconazole, on the pharmacokinetics and cardiovascular safety of tamsulosin

Br J Clin Pharmacol. 2011 Aug;72(2):247-56. doi: 10.1111/j.1365-2125.2011.03988.x.


What is already known about this subject: Tamsulosin metabolism involves both CYP2D6 and 3A4. However, data on potential drug-drug interactions between tamsulosin and inhibitors of CYP2D6 and 3A4 are limited and information on potential pharmacodynamic consequences of such pharmacokinetic interactions is missing.

What this study adds: This study provides information on the drug-drug interactions of tamsulosin with strong CYP2D6 and strong CYP3A4 inhibitors after single dose administration in healthy subjects.

Aim: To determine the effect of the strong CYP2D6 inhibitor paroxetine and strong CYP3A4 inhibitor ketoconazole on the pharmacokinetics and safety (orthostatic challenge) of tamsulosin.

Methods: Two open-label, randomized, two-way crossover studies were conducted in healthy male volunteers (extensive CYP2D6 metabolizers).

Results: Co-administration of multiple oral doses of 20 mg paroxetine once daily with a single oral dose of the 0.4 mg tamsulosin HCl capsule increased the adjusted geometric mean (gMean) values of C(max) and AUC(0,∞) of tamsulosin by factors of 1.34 (90% CI 1.21, 1.49) and 1.64 (90% CI 1.44, 1.85), respectively, and increased the terminal half-life (t(1/2) ) of tamsulosin HCl from 11.4 h to 15.3 h. Co-administration of multiple oral doses of 400 mg ketoconazole once daily with a single oral dose of the 0.4 mg tamsulosin increased the gMean values of C(max) and AUC(0,∞) of tamsulosin by a factor of 2.20 (90% CI 1.96, 2.45) and 2.80 (90% CI 2.56, 3.07), respectively. The terminal half-life was slightly increased from 10.5 h to 11.8 h. These pharmacokinetic changes were not accompanied by clinically significant alterations of haemodynamic responses during orthostatic stress testing.

Conclusion: The exposure to tamsulosin is increased upon co-administration of strong CYP2D6 inhibitors and even more so of strong 3A4 inhibitors, but neither PK alteration was accompanied by clinically significant haemodynamic changes during orthostatic stress testing.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • 14-alpha Demethylase Inhibitors / pharmacokinetics
  • Adrenergic alpha-1 Receptor Antagonists / pharmacokinetics
  • Adult
  • Analysis of Variance
  • Area Under Curve
  • Cardiovascular System / metabolism
  • Cross-Over Studies
  • Cytochrome P-450 CYP2D6 Inhibitors*
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 CYP3A Inhibitors*
  • Double-Blind Method
  • Drug Interactions
  • Half-Life
  • Heart / drug effects*
  • Humans
  • Ketoconazole / pharmacology*
  • Male
  • Middle Aged
  • Paroxetine / pharmacology*
  • Selective Serotonin Reuptake Inhibitors / pharmacokinetics
  • Sulfonamides / pharmacokinetics*
  • Tamsulosin
  • Young Adult


  • 14-alpha Demethylase Inhibitors
  • Adrenergic alpha-1 Receptor Antagonists
  • Cytochrome P-450 CYP2D6 Inhibitors
  • Cytochrome P-450 CYP3A Inhibitors
  • Serotonin Uptake Inhibitors
  • Sulfonamides
  • Paroxetine
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • Tamsulosin
  • Ketoconazole