Drug-drug interaction between tamsulosin and diltiazem, a moderate CYP3A4 inhibitor

Purpose: Tamsulosin, a selective α₁-adrenoceptor antagonist with relatively high affinity for α_1A-subtype, is primarily used for the treatment of lower urinary tract symptoms that are suggestive of benign prostatic hyperplasia (BPH). It is reported that CYP3A4 and CYP2D6 are major metabolic enzymes responsible for the biotransformation of tamsulosin. Diltiazem is known as a moderate inhibitor of CYP3A4. In this study, we investigated the effects of co-administration of diltiazem on the pharmacokinetics of tamsulosin.

Methods: Ten healthy subjects genotyped as homozygous for the CYP2D6 wild-type alleles (CYP2D6*1 or *2) were recruited for the study. In the control phase, each subject received a single oral dose of 0.2 mg tamsulosin. In the diltiazem phase, the subjects were administered an oral dose of 60 mg diltiazem three-times daily for four days. In the study day (day 3), they received a single oral dose of 0.2 mg tamsulosin, one hour after the the morning dose of diltiazem was ingested. Blood samples were collected up to 48 hr after drug intake in each phase, and plasma concentrations of tamsulosin were determined by a validated LC-MS/MS analytical method.

Results: In the diltiazem phase, C_max and AUC_inf of tamsulosin were both 1.7-fold increased than those in the control phase (both P<0.0001). AUC_inf of tamsulosin in the control phase and in the diltiazem phase was 48.2±14.1 ng·hr/mL and 82.2 ± 21.9 ng·hr/mL, respectively. Oral clearance (CL/F) of tamsulosin in the diltiazem phase (2.6 ± 0.6 L/hr) was also significantly decreased than that in the control phase (4.4 ± 1.1 L/hr, P<0.0001). However, half-life (t_1/2) of tamsulosin between two phases were not significantly different.

Conclusion: Co-administration of diltiazem significantly decreased the plasma exposure of tamsulosin by the inhibition of CYP3A4 enzyme.