Impact of CYP3A4*22 Genetic Variant and Plasma microRNA mir-27b Expression Level on Silodosin Steady-State Concentration and Therapy Outcomes in Patients with Benign Prostatic Hyperplasia: A Prospective Observational Trial
Sh. P. Abdullaev,
I. V. Bure,
M. N. Shatokhin,
Sh. P. Abdullaev,
P. O. Bochkov,
S. N. Tuchkova,
K. B. Mirzaev,
O. B. Loran,
D. A. Sychev https://doi.org/10.19163/2307-9266-2025-13-6-487-499
Abstract
Despite the proven efficacy of silodosin for lower urinary tract symptoms (LUTSs), significant interindividual variability in response to pharmacotherapy and the development of adverse events persists. Potential factors for this variability include pharmacogenetic and epigenetic mechanisms regulating drug metabolism.
The aim. To investigate the impact of CYP3A4*22 polymorphism and circulating microRNA miR-27b level on the pharmacokinetics, efficacy, and safety of silodosin in patients with benign prostatic hyperplasia (BPH).
Materials and methods. The study included 98 patients with LUTS due to BPH who were prescribed silodosin 8 mg/day for 8 weeks. IPSS and QoL dynamics, and the frequency of adverse events were assessed. The steady-state minimum concentration of silodosin (Css) was determined by HPLC-MS/MS. Genotyping for CYP3A4*22 was performed by real-time PCR. The expression level of plasma miR-27b was determined using RT-qPCR.
Results. Patients with the CT genotype (12.2%) had significantly higher Css values compared to carriers of the CC genotype (13.44 [6.35; 16.6] vs 6.15 [3.10; 11.31] ng/mL; p = 0.005717). Despite this, the reduction in symptom severity according to IPSS and improvement in QoL were comparable in both groups (p >0.05). No correlation was found between Css and IPSS dynamics (rs = -0.115554, p = 0.257195). MiR-27b levels did not differ between genotypes and did not correlate with either Css or clinical outcomes. The structure of adverse events corresponded to the established safety profile of silodosin; no statistically significant differences were found between genotypic groups.
Conclusion. Carrying the CYP3A4*22 polymorphism is associated with increased silodosin exposure, but the clinical efficacy of therapy remains independent of this genetic marker. Data on the role of miR-27b in regulating pharmacokinetics and clinical outcomes in this population were not confirmed.
Supporting agencies: The work was supported by the Russian Science Foundation grant (project No. 23-15-00310; https://rscf.ru/project/23-15-00310/).
About the Authors
Sh. P. Abdullaev
Russian Medical Academy of Continuous Professional Education.
Russian Federation
Russian Federation
Candidate of Sciences (Medicine), technician of the Department of Endoscopic Urology of Russian Medical Academy of Continuous Professional Education.
2/1 Barrikadnaya Str., bldg. 1, Moscow, Russia, 125993.
I. V. Bure
1. Russian Medical Academy of Continuous Professional Education.
2. Sechenov First Moscow State Medical University (Sechenov University).
Russian Federation
Russian Federation
Candidate of Sciences (Biology), Leading Researcher of the Laboratory of Medical Genetics of the Sechenov First Moscow State Medical University (Sechenov University; Leading Researcher of the Department of Predictive and Prognostic Biomarkers of the Research Institute of Molecular and Personalized Medicine of the Russian Medical Academy of Continuous Professional Education.
2/1 Barrikadnaya Str., bldg. 1, Moscow, Russia, 125993.
8 Trubetskaya Str., bldg. 2, Moscow, Russia, 119991.
M. N. Shatokhin
1. Russian Medical Academy of Continuous Professional Education.
2. Central Hospital «Russian Railways-Medicine».
Russian Federation
Russian Federation
Doctor of Sciences (Medicine), Professor, Professor of the Department of Endoscopic Urology of Russian Medical Academy of Continuous Professional Education; urologist andrologist of Central Hospital «Russian Railways-Medicine».
2/1 Barrikadnaya Str., bldg. 1, Moscow, Russia, 125993.
84 Volokolamskoye Hwy., Moscow, Russia, 125310.
Sh. P. Abdullaev
1. Russian Medical Academy of Continuous Professional Education.
2. Russian Scientific Center of Surgery named after Academician B.V. Petrovsky.
Russian Federation
Russian Federation
Candidate of Sciences (Biology), Head of the Department of Predictive and Prognostic Biomarkers of the Research Institute of Molecular and Personalized Medicine of the Russian Medical Academy of Continuous Professional Education; Leading Researcher of the Department of Pharmacogenetics and Personalized Therapy at the World-class Center for Genomic Research "Center for Predictive Genetics, Pharmacogenetics and Personalized Therapy", Russian Scientific Center of Surgery named after Academician B.V. Petrovsky.
2/1 Barrikadnaya Str., bldg. 1, Moscow, Russia, 125993.
2 Abrikosovsky Ln., Moscow, Russia, 119991.
P. O. Bochkov
1. Russian Medical Academy of Continuous Professional Education.
2. Moscow Scientific and Practical Laboratory Research Center.
Russian Federation
Russian Federation
Candidate of Sciences (Biology), Leading Researcher of the Department of Predictive and Prognostic Biomarkers, Research Institute of Molecular and Personalized Medicine of Russian Medical Academy of Continuous Professional Education; Deputy Director for Science of the Moscow Scientific and Practical Laboratory Research Center (Moscow, Russia).
2/1 Barrikadnaya Str., bldg. 1, Moscow, Russia, 125993.
49 Orekhovy Blvd., bldg. 1, Moscow, Russia, 115580.
S. N. Tuchkova
1. Russian Medical Academy of Continuous Professional Education.
2. Russian Scientific Center of Surgery named after Academician B.V. Petrovsky.
Russian Federation
Russian Federation
Junior Researcher of the Department of Predictive and Prognostic Biomarkers of the Research Institute of Molecular and Personalized Medicine of Russian Medical Academy of Continuous Professional Education; Junior Researcher of the Department of Pharmacogenetics and Personalized Therapy at the World-class Center for Genomic Research "Center for Predictive Genetics, Pharmacogenetics and Personalized Therapy", Russian Scientific Center of Surgery named after Academician B.V. Petrovsky.
2/1 Barrikadnaya Str., bldg. 1, Moscow, Russia, 125993.
2 Abrikosovsky Ln., Moscow, Russia, 119991.
K. B. Mirzaev
1. Russian Medical Academy of Continuous Professional Education.
2. Russian Scientific Center of Surgery named after Academician B.V. Petrovsky.
Russian Federation
Russian Federation
Doctor of Sciences (Medicine), Assistant Professor, Vice Rector for Research and Innovation, Director of the Research Institute of Molecular and Personalized Medicine, Professor of the Department of Clinical Pharmacology and Therapy named after academician B.E. Votchal, Russian Medical Academy of Continuous Professional Education; Deputy Head of the Department of Pharmacogenetics and Personalized Therapy at the World-class Center for Genomic Research "Center for Predictive Genetics, Pharmacogenetics and Personalized Therapy", Russian Scientific Center of Surgery named after Academician B.V. Petrovsky.
2/1 Barrikadnaya Str., bldg. 1, Moscow, Russia, 125993.
2 Abrikosovsky Ln., Moscow, Russia, 119991.
O. B. Loran
Russian Medical Academy of Continuous Professional Education.
Russian Federation
Russian Federation
Doctor of Sciences (Medicine), Professor, Head of the Department of Urology and Surgical Andrology of Russian Medical Academy of Continuous Professional Education; Academician of the Russian Academy of Sciences.
2/1 Barrikadnaya Str., bldg. 1, Moscow, Russia, 125993.
D. A. Sychev
1. Russian Medical Academy of Continuous Professional Education.
2. Russian Scientific Center of Surgery named after Academician B.V. Petrovsky.
Russian Federation
Russian Federation
Doctor of Sciences (Medicine), Professor, Rector, Head of Department of Clinical Pharmacology and Therapy named after academician B.E. Votchal, Russian Medical Academy of Continuous Professional Education; Academician of the Russian Academy of Sciences; Head of the Department of Pharmacogenetics and Personalized Therapy at the World-class Center for Genomic Research "Center for Predictive Genetics, Pharmacogenetics and Personalized Therapy", Russian Scientific Center of Surgery named after Academician B.V. Petrovsky.
2/1 Barrikadnaya Str., bldg. 1, Moscow, Russia, 125993.
2 Abrikosovsky Ln., Moscow, Russia, 119991.
References
1. Chughtai B, Forde JC, Thomas DD, Laor L, Hossack T, Woo HH, Te AE, Kaplan SA. Benign prostatic hyperplasia. Nat Rev Dis Primers. 2016;2:16031. DOI: 10.1038/nrdp.2016.31
2. Sandhu JS, Bixler BR, Dahm P, Goueli R, Kirkby E, Stoffel JT, Wilt TJ. Management of Lower Urinary Tract Symptoms Attributed to Benign Prostatic Hyperplasia (BPH): AUA Guideline Amendment 2023. J Urol. 2024;211(1):11–19. DOI: 10.1097/JU.0000000000003698
3. Lee SWH, Chan EMC, Lai YK. The global burden of lower urinary tract symptoms suggestive of benign prostatic hyperplasia: A systematic review and meta-analysis. Sci Rep. 2017;7(1):7984. DOI: 10.1038/s41598-017-06628-8
4. Wei H, Zhu C, Huang Q, Yang J, Li YT, Zhang YG, Li BH, Zi H. Global, regional, and national burden of benign prostatic hyperplasia from 1990 to 2021 and projection to 2035. BMC Urol. 2025;25:34. DOI: 10.1186/s12894-025-01715-9
5. Launer BM, McVary KT, Ricke WA, Lloyd GL. The rising worldwide impact of benign prostatic hyperplasia. BJU Int. 2021;127(6):722–8. DOI: 10.1111/bju.15286
6. Jung JH, Kim J, MacDonald R, Reddy B, Kim MH, Dahm P. Silodosin for the treatment of lower urinary tract symptoms in men with benign prostatic hyperplasia. Cochrane Database Syst Rev. 2017;11(11):CD012615. DOI: 10.1002/14651858.CD012615.pub2
7. Yoosuf BT, Panda AK, Kt MF, Bharti SK, Devana SK, Bansal D. Comparative efficacy and safety of alpha-blockers as monotherapy for benign prostatic hyperplasia: a systematic review and network meta-analysis. Sci Rep. 2024;14(1):11116. DOI: 10.1038/s41598-024-61977-5. Erratum in: Sci Rep. 2024;14(1):12932. DOI: 10.1038/s41598-024-63406-z
8. Klyushova LS, Perepechaeva ML, Grishanova AY. The Role of CYP3A in Health and Disease. Biomedicines. 2022;10(11):2686. DOI: 10.3390/biomedicines10112686
9. Mulder TAM, van Eerden RAG, de With M, Elens L, Hesselink DA, Matic M, Bins S, Mathijssen RHJ, van Schaik RHN. CYP3A4∗22 Genotyping in Clinical Practice: Ready for Implementation? Front Genet. 2021;12:711943. DOI: 10.3389/fgene.2021.711943
10. Pratt VM, Cavallari LH, Fulmer ML, Gaedigk A, Hachad H, Ji Y, Kalman LV, Ly RC, Moyer AM, Scott SA, van Schaik RHN, Whirl-Carrillo M, Weck KE. CYP3A4 and CYP3A5 Genotyping Recommendations: A Joint Consensus Recommendation of the Association for Molecular Pathology, Clinical Pharmacogenetics Implementation Consortium, College of American Pathologists, Dutch Pharmacogenetics Working Group of the Royal Dutch Pharmacists Association, European Society for Pharmacogenomics and Personalized Therapy, and Pharmacogenomics Knowledgebase. J Mol Diagn. 2023;25(9):619–29. DOI: 10.1016/j.jmoldx.2023.06.008
11. Wang D, Sadee W. CYP3A4 intronic SNP rs35599367 (CYP3A4*22) alters RNA splicing. Pharmacogenet Genomics. 2016;26(1):40–3. DOI: 10.1097/FPC.0000000000000183
12. Ekström L, Skilving I, Ovesjö ML, Aklillu E, Nylén H, Rane A, Diczfalusy U, Björkhem-Bergman L. miRNA-27b levels are associated with CYP3A activity in vitro and in vivo. Pharmacol Res Perspect. 2015;3(6):e00192. DOI: 10.1002/prp2.192
13. Ito K, Ohtani H, Sawada Y. Assessment of alpha1-adrenoceptor antagonists in benign prostatic hyperplasia based on the receptor occupancy theory. Br J Clin Pharmacol. 2007;63(4):394–403. DOI: 10.1111/j.1365-2125.2006.02783.x
14. Korstanje C, Krauwinkel W, van Doesum-Wolters FL. Tamsulosin shows a higher unbound drug fraction in human prostate than in plasma: a basis for uroselectivity? Br J Clin Pharmacol. 2011;72(2):218–25. DOI: 10.1111/j.1365-2125.2010.03870.x
15. Roehrborn CG. Efficacy of alpha-Adrenergic Receptor Blockers in the Treatment of Male Lower Urinary Tract Symptoms. Rev Urol. 2009 Fall;11(Suppl 1):S1–8.
16. Vuichoud C, Loughlin KR. Benign prostatic hyperplasia: epidemiology, economics and evaluation. Can J Urol. 2015;22 Suppl 1:1–6.
17. Lee CL, Kuo HC. Pathophysiology of benign prostate enlargement and lower urinary tract symptoms: Current concepts. Tzu Chi Med J. 2017;29(2):79–83. DOI: 10.4103/tcmj.tcmj_20_17
18. Zastrozhin MS, Skryabin VY, Smirnov VV, Petukhov AE, Pankratenko EP, Zastrozhina AK, Grishina EA, Ryzhikova KA, Bure IV, Golovinskii PA, Koporov SG, Bryun EA, Sychev DA. Effects of plasma concentration of micro-RNA Mir-27b and CYP3A4*22 on equilibrium concentration of alprazolam in patients with anxiety disorders comorbid with alcohol use disorder. Gene. 2020;739:144513. DOI: 10.1016/j.gene.2020.144513
19. Zastrozhin MS, Skryabin V, Smirnov V, Zastrozhina AK, Kaverina EV, Klepikov DA, Grishina EA, Ryzhikova KA, Bure IV, Bryun EA, Sychev DA. Impact of the Omics-Based Biomarkers on the Fluvoxamine's Steady-State Concentration, Efficacy and Safety in Patients with Affective Disorders Comorbid with Alcohol Use Disorder. Psychopharmacol Bull. 2021;51(1):69–80.
20. Zendjabil M. Preanalytical, analytical and postanalytical considerations in circulating microRNAs measurement. Biochem Med (Zagreb). 2024;34(2):020501. DOI: 10.11613/BM.2024.020501
21. Faraldi M, Gomarasca M, Sansoni V, Perego S, Banfi G, Lombardi G. Normalization strategies differently affect circulating miRNA profile associated with the training status. Sci Rep. 2019;9:1584. DOI: 10.1038/s41598-019-38505-x
22. Wang Z, Xiang Q, Cui Y, Zhao X, Zhou Y. The influence of UGT2B7, UGT1A8, MDR1, ALDH, ADH, CYP3A4 and CYP3A5 genetic polymorphisms on the pharmacokinetics of silodosin in healthy Chinese volunteers. Drug Metab Pharmacokinet. 2013;28(3):239–43. DOI: 10.2133/dmpk.dmpk-12-rg-106
23. Novara G, Tubaro A, Sanseverino R, Spatafora S, Artibani W, Zattoni F, Montorsi F, Chapple CR. Systematic review and meta-analysis of randomized controlled trials evaluating silodosin in the treatment of non-neurogenic male lower urinary tract symptoms suggestive of benign prostatic enlargement. World J Urol. 2013;31(4):997–1008. DOI: 10.1007/s00345-012-0944-8. Erratum in: World J Urol. 2013;31(4):1009.
24. Montorsi F, Gandaglia G, Chapple C, Cruz F, Desgrandchamps F, Llorente C. Effectiveness and safety of silodosin in the treatment of lower urinary tract symptoms in patients with benign prostatic hyperplasia: A European phase IV clinical study (SiRE study). Int J Urol. 2016;23(7):572–9. DOI: 10.1111/iju.13088
25. Akhtar OS, Singh V, Bhojani KA, Dharmadhikari S, Bhargave C, Mane A, Mehta S. A Comprehensive Review of the Clinical Evidence on the Efficacy, Effectiveness, and Safety of Silodosin for the Treatment of Benign Prostatic Hyperplasia. Cureus. 2025;17(6):e85445. DOI: 10.7759/cureus.85445
Review
For citations:
Abdullaev Sh.P., Bure I.V., Shatokhin M.N., Abdullaev Sh.P., Bochkov P.O., Tuchkova S.N., Mirzaev K.B., Loran O.B., Sychev D.A. Impact of CYP3A4*22 Genetic Variant and Plasma microRNA mir-27b Expression Level on Silodosin Steady-State Concentration and Therapy Outcomes in Patients with Benign Prostatic Hyperplasia: A Prospective Observational Trial. Pharmacy & Pharmacology. 2025;13(6):487-499. (In Russ.) https://doi.org/10.19163/2307-9266-2025-13-6-487-499
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