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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.
• 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 Cmax 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 (t1/2) of tamsulosin HCl from 11.4 h to 15.3 h. Co-administration of multiple oral doses of 400 mg ketoconazole once dailywith a single oral dose of the 0.4 mg tamsulosin increased the gMean values of Cmax 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.
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Lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH) are common among elderly males [1–3]. The medical treatment of LUTS/BPH mainly involves inhibition of the enzyme 5α-reductase to reduce prostate size  and α1-adrenoceptor antagonists. The latter are more frequently used as they reduce LUTS more effectively than the 5α-reductase inhibitors in most patients . Globally, tamsulosin is the most frequently prescribed α1-adrenoceptor antagonist for the treatment of LUTS/BPH. It is generally well tolerated, and cardiovascular side effects occur only rarely in the standard therapeutic dose of 0.4 mg day−1[6, 7].
The average man receiving an α1-adrenoceptor antagonist prescription for the treatment of LUTS/BPH is in his mid-sixties and frequently has comorbidities and associated comedications [8, 9]. Such comedications may give rise to pharmacodynamic and/or pharmacokinetic drug–drug interactions which reduce the otherwise good tolerability. For example, among potential pharmacodynamic interactions it has been observed that the incidence of adverse events with tamsulosin quadruples when other α1-adrenoceptor antagonists or verapamil (which has α1-adrenoceptor antagonist effects in therapeutic doses) are used concomitantly . In contrast, pharmacodynamic interactions with other blood pressure lowering drugs are rare [8, 10].
The pharmacokinetic profile of tamsulosin has been reviewed comprehensively recently  and it has also been studied in a paediatric population . Its metabolism involves both CYP2D6 and 3A4 [13, 14] and yields at least some compounds with α1-adrenoceptor antagonist properties  but these metabolites have only low abundance in man. Nevertheless, only limited data are available on potential drug–drug interactions between tamsulosin and inhibitors of CYP2D6 and 3A4. Only one study with 400 mg of the weak CYP3A4 inhibitor cimetidine has been reported . While that study indicated a limited potential for interaction with CYP 3A4 inhibitors, it lacked information on potential pharmacodynamic consequences of such pharmacokinetic interactions. Dedicated studies with strong inhibitors of CYP 2D6 or 3A4 are missing. Therefore, we have performed drug–drug interaction studies with paroxetine, a mechanism based inhibitor  and ketoconazole, which included not only pharmacokinetic but also pharmacodynamic safety assessments including forced orthostatic stress testing.
Preliminary results of these studies have been reported to the British Pharmacological Society [18, 19].