Study of allelic variants of the CYP2D6 and CYP3A genes on the effectiveness and safety of tamsulosin therapy in patients with BPH: results of a pilot study

Introduction. Tamsulosin is a member of the group of selective α1-adrenoblockers. Tamsulosin monotherapy is the most common first-line option in patients with lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) and can be used regardless on severity of LUTS. The CYP2D6, CYP3A4, and CYP3A5 enzymes are involved in the metabolism of tamsulosin. Carriage of different allelic variants of CYP2D6, CYP3A4 and CYP3A5, involved in its metabolism, may potentially affect the variability of efficacy and safety of the drug.

Aim. To evaluate the effect of carriage of allelic variants of cytochrome P450 superfamily enzyme genes (CYP2D6*3, CYP2D6*4, CYP2D6*9, CYP2D6*10, CYP2D6*41, CYP3A4*3, CYP3A4*22 and CYP3A5*3) on the efficiency and safety of tamsulosin in patients with LUTS associated with BPH.

Materials and Methods. All phases of the study were completed by 106 patients with LUTS/BPH (N40 according to ICD 10). All patients received monotherapy with tamsulosin 0.4 mg/day for a minimum of 8 weeks. Based on the severity of symptoms, they were divided into two groups using the International Prostate Symptom Score (IPSS). In Group 1, there were patients with moderate symptoms (IPSS score of 8-19) (n=57), while Group 2 consisted of those with severe symptoms (IPSS score >20) (n=49). Treatment outcomes were assessed using the IPSS score with determination of quality of life (QoL), transrectal ultrasound with evaluation of prostate volume and residual urine, and uroflowmetry. Follow-up visits were at 2, 4, and 8 weeks after the start of therapy. Genotyping of all patients was performed using polymerase chain reaction to determine the CYP2D6 (*3, *4, *9, *10, and *41), CYP3A4 (*3, *22), and CYP3A5*3 markers.

Results. In the group of patients with moderate symptoms, carriers of the CYP2D6*10 and CYP2D6*41 polymorphisms showed a significantly greater reduction in symptoms according to the overall IPSS score at 8 weeks (p=0.046) and in the micturition symptom subscale starting from 4 weeks of treatment (p<0.05). Carriers of the CYP2D6*10 polymorphism in both groups were associated with a decrease in residual urine volume at 8 weeks (p<0.05). The presence of the CYP3A5*3 variant in those with severe symptoms significantly improved quality of life during therapy. Allelic variants of the CYP2D6 and CYP3A genes did not affect the frequency of adverse events.

Conclusion. The results obtained by calculating the prognostic significance of individual polymorphic markers pointed to the contribution of CYP2D6*10 and CYP2D6*41. Tamsulosin therapy is more effective in patients with LUTS who are carriers of these allele variants. The safety parameters of tamsulosin were not influenced by the studied polymorphic variants. It was found that CYP3A5*3 was associated with an increase in the subjective assessment of the patient's quality of life, but it is too early to draw final conclusions. The issue of the contribution of genetic factors to the efficiency and safety of treatment of LUTS in BPH requires further study with a larger sample size and analyzed parameters.