TY  - JOUR
T1  - Impact of CYP450 and Transporter Polymorphisms on Dutasteride–Tamsulosin Exposure and Tolerability
A1  - Nabin Karki
A1  - Suman Gurung
A1  - Tenzing Sherpa
A1  - Prakash Adhikari
JF  - Specialty Journal of Pharmacognosy, Phytochemistry, and Biotechnology
JO  - Spec J Pharmacogn Phytochem Biotechnol
SN  - 3062-441X
Y1  - 2025
VL  - 5
IS  - 1
DO  - 10.51847/7trSgV8UhZ
SP  - 139
EP  - 149
N2  - Dutasteride and tamsulosin constitute a widely used first-line combination therapy for benign prostatic hyperplasia (BPH). Although this regimen is generally more effective than either drug alone, it is also associated with a higher frequency of adverse drug reactions (ADRs). Regulatory agencies—including the U.S. Food and Drug Administration and the European Medicines Agency—advise caution when prescribing tamsulosin to CYP2D6 poor metabolizers (PMs) receiving CYP3A4 inhibitors. However, no detailed pharmacogenetic dosing recommendations currently exist for tamsulosin, and there is an absence of pharmacogenetic guidance for dutasteride. To address this gap, we examined the pharmacokinetic profile and safety of fixed-dose dutasteride/tamsulosin (0.5 mg/0.4 mg) in relation to 76 polymorphisms across 17 candidate pharmacogenes.

Seventy-nine healthy male participants were enrolled in three phase-I, randomized, crossover, open-label bioequivalence studies, each with a different design: a single-dose fed trial, a single-dose fasting trial, and a multiple-dose trial. Notably, CYP2D6 PMs (genotypes *4/*4 and *4/*5) and intermediate metabolizers (IMs; *1/*4, *1/*5, *4/*15) displayed significantly elevated AUC (p = 0.004), prolonged t₁/₂ (p = 0.008), and reduced apparent clearance (Cl/F) (p = 0.006) compared with normal metabolizers (*1/*1) and ultrarapid metabolizers (*1/*1 × 2), after correction for multiple comparisons. Fed-state administration also resulted in a significantly longer tmax than fasting conditions. Additional nominal associations were observed between dutasteride exposure and CYP3A4/CYP3A5 genotypes, and between tamsulosin concentrations and ABCG2, CYP3A5, and SLC22A1 genotypes. No significant genotype–ADR relationship was identified; however, adverse events were more common in the multiple-dose study. Based on these findings, dose adjustments may be beneficial for CYP2D6 PMs to enhance safety and for UMs to improve therapeutic efficacy. Further research is required to validate the remaining pharmacogenetic associations.
UR  - https://galaxypub.co/article/impact-of-cyp450-and-transporter-polymorphisms-on-dutasteridetamsulosin-exposure-and-tolerability-fdrwzv4ajtjpsrv
ER  -