title: Effects of strong CYP2D6 and 3A4 inhibitors, paroxetine and ketoconazole, on the pharmacokinetics and cardiovascular safety of tamsulosin.
abstract: BACKGROUND
  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.
  
  
  CONCLUSIONS
  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.
  
  
  OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co.KG, Ingelheim, Germany. joachim.troost@boehringer-ingelheim.com
authors.forename: Joachim
authors.initials: J
authors.lastname: Troost
authors.forename: Shinji
authors.initials: S
authors.lastname: Tatami
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Tsuda
authors.forename: Michaela
authors.initials: M
authors.lastname: Mattheus
authors.forename: Ludwig
authors.initials: L
authors.lastname: Mehlburger
authors.forename: Martina
authors.initials: M
authors.lastname: Wein
authors.forename: Martin C
authors.initials: MC
authors.lastname: Michel
mesh_terms: D058888:14-alpha Demethylase Inhibitors / Q000493:pharmacokinetics; D058668:Adrenergic alpha-1 Receptor Antagonists / Q000493:pharmacokinetics; D000328:Adult; D000704:Analysis of Variance; D019540:Area Under Curve; D002319:Cardiovascular System / Q000378:metabolism; D018592:Cross-Over Studies; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D004311:Double-Blind Method; D004347:Drug Interactions; D006207:Half-Life; D006321:Heart / Q000187:drug effects*; D006801:Humans; D007654:Ketoconazole / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D017374:Paroxetine / Q000494:pharmacology*; D017367:Selective Serotonin Reuptake Inhibitors / Q000493:pharmacokinetics; D013449:Sulfonamides / Q000493:pharmacokinetics*; D000077409:Tamsulosin; D055815:Young Adult
chemical_list: D058888:14-alpha Demethylase Inhibitors; D058668:Adrenergic alpha-1 Receptor Antagonists; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D007654:Ketoconazole; D017374:Paroxetine; D017367:Selective Serotonin Reuptake Inhibitors; D013449:Sulfonamides; D000077409:Tamsulosin; C510163:CYP3A4 protein, human