Effects of diltiazem, a moderate inhibitor of CYP3A4, on the pharmacokinetics of tamsulosin in different CYP2D6 genotypes

Tamsulosin, a selective antagonist of the α₁-adrenoceptor, is primarily metabolized by CYP3A4 and CYP2D6, and tamsulosin exposure is significantly increased according to the genetic polymorphism of CYP2D6. In this study, we investigated the effects of diltiazem, a moderate inhibitor of CYP3A4, on the pharmacokinetics of tamsulosin in subjects with different CYP2D6 genotypes. Twenty-three healthy Korean male subjects with CYP2D6*wt/*wt (*wt = *1 or *2) and CYP2D6*10/*10 were enrolled in the prospective, open-label, two-phase parallel pharmacokinetic study. On the first day of study (day 1), each subject received a single 0.2 mg oral dose of tamsulosin. After a washout period of 1 week, on day 8, the subjects were given a 60 mg oral dose of diltiazem three times daily for four days. On day 10, 1 h after the morning dose of diltiazem, they received a single 0.2 mg oral dose of tamsulosin. The pharmacokinetic parameters of tamsulosin in those with and without diltiazem treatment were compared in subjects with different CYP2D6 genotypes. After diltiazem treatment, the C_max and AUC_inf of tamsulosin in each CYP2D6 genotype group were significantly increased (p < 0.0001 for all). The CL/F of tamsulosin was also significantly decreased after diltiazem treatment (both p < 0.0001). However, diltiazem did not affect the t_1/2 of tamsulosin in each genotype group. In conclusion, diltiazem significantly increases exposure to tamsulosin regardless of the genotype of CYP2D6. Dose adjustment in the daily maintenance dose of tamsulosin may improve tolerability and safety in patients receiving diltiazem.