Shokhrukh P Abdullaev, Maksim N Shatokhin, Pavel O Bochkov, Svetlana N Tuchkova, Oleg B Loran, Sherzod P Abdullaev, Karin B Mirzaev, Dmitry A Sychev
{"title":"西洛多辛暴露和疗效的遗传调控：CYP3A4、CYP3A5和UGT2B7多态性在良性前列腺增生管理中的作用","authors":"Shokhrukh P Abdullaev, Maksim N Shatokhin, Pavel O Bochkov, Svetlana N Tuchkova, Oleg B Loran, Sherzod P Abdullaev, Karin B Mirzaev, Dmitry A Sychev","doi":"10.3390/jpm15080386","DOIUrl":null,"url":null,"abstract":"<p><p><b>Objectives</b>: Silodosin, a selective α1A-adrenoceptor antagonist, is used to treat lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH). Genetic polymorphisms in drug-metabolizing enzymes and transporters may contribute to interindividual variability in its efficacy and safety. This study aimed to investigate the influence of CYP3A4, CYP3A5, UGT2B7, and ABCB1 polymorphisms on silodosin pharmacokinetics, efficacy, and safety in Russian patients with BPH. <b>Methods</b>: A prospective observational study included 103 Russian male patients with moderate-to-severe LUTS (IPSS > 8) due to BPH, treated with silodosin (8 mg daily) for 8 weeks. Genotyping for CYP3A4*1B, CYP3A4*22, CYP3A5*3, UGT2B7 (rs73823859, rs7439366, and rs7668282), and ABCB1 (rs4148738, rs1045642, rs2032582, and rs1128503) was performed using real-time PCR. The silodosin minimum steady-state plasma concentration (Css min) was measured via HPLC-MS. Efficacy was evaluated by the International Prostate Symptom Score (IPSS), quality of life scale, maximum urinary flow rate (Qmax), residual urine volume (RUV), and prostate volume at the baseline and week 8. Adverse drug reactions (ADRs) were recorded. <b>Results</b>: CYP3A4*22 CT carriers (n = 6) exhibited higher Css min (17.59 ± 2.98 vs. 9.0 ± 10.47 ng/mL, <i>p</i> = 0.049) but less absolute IPSS improvement (<i>p</i> < 0.05), likely due to higher baseline symptom severity. However, the change in IPSS (ΔIPSS<sub>1-4</sub>) from the baseline to week 8 did not differ significantly (-5.78 ± 5.29 vs. -6.0 ± 4.54, <i>p</i> = 0.939). CYP3A5*3 GG homozygotes (n = 96) showed greater ΔIPSS<sub>1-4</sub> improvement (-6.25 ± 4.60 vs. 0.0 ± 9.53, <i>p</i> = 0.042) and a lower IPSS at day 28 (7.64 ± 4.50 vs. 20.0 ± 6.55, <i>p</i> < 0.001). UGT2B7 rs7439366 TT carriers (n = 34) had an improved Qmax (ΔQmax<sub>1-4</sub> 5.4 vs. 3.3 and 2.0 mL/s for CC and CT, <i>p</i> = 0.041). ABCB1 1236C>T TT homozygotes (n = 25) showed a trend toward reduced RUV (<i>p</i> = 0.053). No polymorphisms were associated with adverse drug reactions (15 events in 42 patients, 35.7%). <b>Conclusions</b>: Genetic polymorphisms CYP3A4*22, CYP3A5*3, and UGT2B7 rs7439366 may modulate silodosin pharmacokinetics and efficacy parameters in BPH patients but not safety. Larger-scale studies are warranted to validate these initial findings.</p>","PeriodicalId":16722,"journal":{"name":"Journal of Personalized Medicine","volume":"15 8","pages":""},"PeriodicalIF":3.0000,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12387821/pdf/","citationCount":"0","resultStr":"{\"title\":\"Genetic Modulation of Silodosin Exposure and Efficacy: The Role of CYP3A4, CYP3A5, and UGT2B7 Polymorphisms in Benign Prostatic Hyperplasia Management.\",\"authors\":\"Shokhrukh P Abdullaev, Maksim N Shatokhin, Pavel O Bochkov, Svetlana N Tuchkova, Oleg B Loran, Sherzod P Abdullaev, Karin B Mirzaev, Dmitry A Sychev\",\"doi\":\"10.3390/jpm15080386\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p><b>Objectives</b>: Silodosin, a selective α1A-adrenoceptor antagonist, is used to treat lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH). Genetic polymorphisms in drug-metabolizing enzymes and transporters may contribute to interindividual variability in its efficacy and safety. This study aimed to investigate the influence of CYP3A4, CYP3A5, UGT2B7, and ABCB1 polymorphisms on silodosin pharmacokinetics, efficacy, and safety in Russian patients with BPH. <b>Methods</b>: A prospective observational study included 103 Russian male patients with moderate-to-severe LUTS (IPSS > 8) due to BPH, treated with silodosin (8 mg daily) for 8 weeks. Genotyping for CYP3A4*1B, CYP3A4*22, CYP3A5*3, UGT2B7 (rs73823859, rs7439366, and rs7668282), and ABCB1 (rs4148738, rs1045642, rs2032582, and rs1128503) was performed using real-time PCR. The silodosin minimum steady-state plasma concentration (Css min) was measured via HPLC-MS. Efficacy was evaluated by the International Prostate Symptom Score (IPSS), quality of life scale, maximum urinary flow rate (Qmax), residual urine volume (RUV), and prostate volume at the baseline and week 8. Adverse drug reactions (ADRs) were recorded. <b>Results</b>: CYP3A4*22 CT carriers (n = 6) exhibited higher Css min (17.59 ± 2.98 vs. 9.0 ± 10.47 ng/mL, <i>p</i> = 0.049) but less absolute IPSS improvement (<i>p</i> < 0.05), likely due to higher baseline symptom severity. However, the change in IPSS (ΔIPSS<sub>1-4</sub>) from the baseline to week 8 did not differ significantly (-5.78 ± 5.29 vs. -6.0 ± 4.54, <i>p</i> = 0.939). CYP3A5*3 GG homozygotes (n = 96) showed greater ΔIPSS<sub>1-4</sub> improvement (-6.25 ± 4.60 vs. 0.0 ± 9.53, <i>p</i> = 0.042) and a lower IPSS at day 28 (7.64 ± 4.50 vs. 20.0 ± 6.55, <i>p</i> < 0.001). UGT2B7 rs7439366 TT carriers (n = 34) had an improved Qmax (ΔQmax<sub>1-4</sub> 5.4 vs. 3.3 and 2.0 mL/s for CC and CT, <i>p</i> = 0.041). ABCB1 1236C>T TT homozygotes (n = 25) showed a trend toward reduced RUV (<i>p</i> = 0.053). No polymorphisms were associated with adverse drug reactions (15 events in 42 patients, 35.7%). <b>Conclusions</b>: Genetic polymorphisms CYP3A4*22, CYP3A5*3, and UGT2B7 rs7439366 may modulate silodosin pharmacokinetics and efficacy parameters in BPH patients but not safety. Larger-scale studies are warranted to validate these initial findings.</p>\",\"PeriodicalId\":16722,\"journal\":{\"name\":\"Journal of Personalized Medicine\",\"volume\":\"15 8\",\"pages\":\"\"},\"PeriodicalIF\":3.0000,\"publicationDate\":\"2025-08-18\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12387821/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Personalized Medicine\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.3390/jpm15080386\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"HEALTH CARE SCIENCES & SERVICES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Personalized Medicine","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.3390/jpm15080386","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"HEALTH CARE SCIENCES & SERVICES","Score":null,"Total":0}
引用次数: 0
摘要
目的：西洛多辛是一种选择性α 1a -肾上腺素受体拮抗剂，用于治疗与良性前列腺增生（BPH）相关的下尿路症状（LUTS）。药物代谢酶和转运体的遗传多态性可能导致其有效性和安全性的个体差异。本研究旨在探讨CYP3A4、CYP3A5、UGT2B7和ABCB1多态性对西洛多辛在俄罗斯BPH患者中的药代动力学、疗效和安全性的影响。方法：一项前瞻性观察研究纳入103名俄罗斯男性患者，他们因BPH而患有中重度LUTS (IPSS >8)，接受西洛多辛（8mg /天）治疗8周。对CYP3A4*1B、CYP3A4*22、CYP3A5*3、UGT2B7 （rs73823859、rs7439366、rs7668282）和ABCB1 （rs4148738、rs1045642、rs2032582、rs1128503）基因进行实时PCR分型。采用高效液相色谱-质谱法测定西洛多辛最低稳态血浆浓度（cssmin）。通过基线和第8周的国际前列腺症状评分（IPSS）、生活质量量表、最大尿流率（Qmax）、剩余尿量（RUV）和前列腺体积来评估疗效。记录药物不良反应（adr）。结果：CYP3A4*22 CT携带者（n = 6）表现出较高的cssmin(17.59±2.98比9.0±10.47 ng/mL, p = 0.049)，但绝对IPSS改善较少（p < 0.05），可能是由于基线症状严重程度较高。然而，IPSS （ΔIPSS1-4）从基线到第8周的变化没有显著差异（-5.78±5.29 vs -6.0±4.54,p = 0.939）。CYP3A5* 3gg纯合子（n = 96）更显著ΔIPSS1-4改善（-6.25±4.60 vs. 0.0±9.53,p = 0.042），第28天IPSS降低（7.64±4.50 vs. 20.0±6.55,p < 0.001）。UGT2B7 rs7439366 TT携带者（n = 34） Qmax提高（ΔQmax1-4 5.4 vs. 3.3和2.0 mL/s， CC和CT， p = 0.041）。ABCB1 1236C>T TT纯合子（n = 25）有RUV降低的趋势（p = 0.053）。无多态性与药物不良反应相关（42例患者15例，占35.7%）。结论：基因多态性CYP3A4*22、CYP3A5*3和UGT2B7 rs7439366可能调节西洛多星在BPH患者中的药代动力学和疗效参数，但不影响安全性。有必要进行更大规模的研究来验证这些初步发现。
Genetic Modulation of Silodosin Exposure and Efficacy: The Role of CYP3A4, CYP3A5, and UGT2B7 Polymorphisms in Benign Prostatic Hyperplasia Management.
Objectives: Silodosin, a selective α1A-adrenoceptor antagonist, is used to treat lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH). Genetic polymorphisms in drug-metabolizing enzymes and transporters may contribute to interindividual variability in its efficacy and safety. This study aimed to investigate the influence of CYP3A4, CYP3A5, UGT2B7, and ABCB1 polymorphisms on silodosin pharmacokinetics, efficacy, and safety in Russian patients with BPH. Methods: A prospective observational study included 103 Russian male patients with moderate-to-severe LUTS (IPSS > 8) due to BPH, treated with silodosin (8 mg daily) for 8 weeks. Genotyping for CYP3A4*1B, CYP3A4*22, CYP3A5*3, UGT2B7 (rs73823859, rs7439366, and rs7668282), and ABCB1 (rs4148738, rs1045642, rs2032582, and rs1128503) was performed using real-time PCR. The silodosin minimum steady-state plasma concentration (Css min) was measured via HPLC-MS. Efficacy was evaluated by the International Prostate Symptom Score (IPSS), quality of life scale, maximum urinary flow rate (Qmax), residual urine volume (RUV), and prostate volume at the baseline and week 8. Adverse drug reactions (ADRs) were recorded. Results: CYP3A4*22 CT carriers (n = 6) exhibited higher Css min (17.59 ± 2.98 vs. 9.0 ± 10.47 ng/mL, p = 0.049) but less absolute IPSS improvement (p < 0.05), likely due to higher baseline symptom severity. However, the change in IPSS (ΔIPSS1-4) from the baseline to week 8 did not differ significantly (-5.78 ± 5.29 vs. -6.0 ± 4.54, p = 0.939). CYP3A5*3 GG homozygotes (n = 96) showed greater ΔIPSS1-4 improvement (-6.25 ± 4.60 vs. 0.0 ± 9.53, p = 0.042) and a lower IPSS at day 28 (7.64 ± 4.50 vs. 20.0 ± 6.55, p < 0.001). UGT2B7 rs7439366 TT carriers (n = 34) had an improved Qmax (ΔQmax1-4 5.4 vs. 3.3 and 2.0 mL/s for CC and CT, p = 0.041). ABCB1 1236C>T TT homozygotes (n = 25) showed a trend toward reduced RUV (p = 0.053). No polymorphisms were associated with adverse drug reactions (15 events in 42 patients, 35.7%). Conclusions: Genetic polymorphisms CYP3A4*22, CYP3A5*3, and UGT2B7 rs7439366 may modulate silodosin pharmacokinetics and efficacy parameters in BPH patients but not safety. Larger-scale studies are warranted to validate these initial findings.
期刊介绍：
Journal of Personalized Medicine (JPM; ISSN 2075-4426) is an international, open access journal aimed at bringing all aspects of personalized medicine to one platform. JPM publishes cutting edge, innovative preclinical and translational scientific research and technologies related to personalized medicine (e.g., pharmacogenomics/proteomics, systems biology). JPM recognizes that personalized medicine—the assessment of genetic, environmental and host factors that cause variability of individuals—is a challenging, transdisciplinary topic that requires discussions from a range of experts. For a comprehensive perspective of personalized medicine, JPM aims to integrate expertise from the molecular and translational sciences, therapeutics and diagnostics, as well as discussions of regulatory, social, ethical and policy aspects. We provide a forum to bring together academic and clinical researchers, biotechnology, diagnostic and pharmaceutical companies, health professionals, regulatory and ethical experts, and government and regulatory authorities.
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