Association of CYP3A4*1B, CYP3A4*22 and CYP3A5*3 polymorphisms carriage with efficacy and safety of tamsulosin in patients with benign prostatic hyperplasia

S. Abdullaev, M. Shatokhin, O. L. Sigailo, S. Abdullaev, P. O. Bochkov, S. N. Tuchkova, O. V. Teodorovich, O. B. Loran, D. Sychev
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Abstract

Tamsulosin is a first-line drug in the treatment of lower urinary tract symptoms (LUTS) in benign prostatic hyperplasia (BPH). Despite high estimates of its efficacy and safety, it rates may vary due to genetic polymorphisms of genes for the enzymes involved in the drugs metabolism.The aim of the work was to evaluate the carriage influence of genes polymorphisms of the CYP3A enzymes group of tamsulosin metabolizers on the efficacy and safety of therapy in patients with LUTS in BPH.Materials and methods. A total of 142 patients with LUTS, with an established BPH diagnosis (N40 according to ICD-10) were included in the study and underwent all stages. All patients received monotherapy with tamsulosin 0.4 mg/day for at least 8 weeks. An IPSS questionnaire with the definition of quality of life, a prostate ultrasound with the determination of the prostate volume and residual urine, as well as uroflowmetry, were used to evaluate the results of the treatment. Controls were performed at 2, 4 and 8 weeks from the start of the therapy. The carriage of polymorphic markers CYP3A4 (*1B, *22) and CYP3A5*3 was determined in patients; HPLC was used to determine drug concentrations in blood plasma and levels of cortisol and its metabolite 6-beta-hydroxycortisol in urine to assess the phenotypic activity of CYP3A.Results. No statistically significant associations between CYP3A phenotype (defined by CYP3A4 and CYP3A5 genotypes) and clinical parameters of the tamsulosin therapy efficacy and the safety assessment in the studied sample of patients were found (p >0.05). Similar data were obtained for individual variants of CYP3A4*1B, CYP3A4*22, CYP3A5*3 (p >0.05). The comparison of the tamsulosin residual equilibrium concentration values in patients in the study sample with respect to the carriers of CYP3A4 and CYP3A5 gene variants did not reveal the presence of significant differences in either CYP3A phenotypes  and carriers and non-carriers of individual CYP3A4*1B (p=0.57), CYP3A4*22 (p=0.37) and CYP3A5*3 (p=0.76) variants. No association was found between the metabolic ratio of 6-beta-hydroxycortisol / cortisol in urine and the CYP3A phenotype encoded by a combination of genotypes of CYP3A4 and CYP3A5 gene variants (p >0.05).Conclusion. A possible association between the carriage of CYP3A4*1B, CYP3A4*22, CYP3A5*3 variants, a CYP3A activity assessed by the content of an endogenous substrate of this isoenzyme and its metabolite in urine, the level of plasma concentration of the drug, and the efficacy and safety of tamsulosin, has not been confirmed. The contribution of CYP3A4 and CYP3A5 genetic polymorphisms to clinical parameters of the tamsulosin therapy requires a further study.
CYP3A4*1B、CYP3A4*22 和 CYP3A5*3 多态性载体与良性前列腺增生患者服用坦索罗辛的疗效和安全性的关系
坦索罗辛是治疗良性前列腺增生症(BPH)下尿路症状(LUTS)的一线药物。本研究旨在评估坦索罗辛代谢酶组 CYP3A 基因多态性对良性前列腺增生症 LUTS 患者疗效和安全性的影响。该研究共纳入了 142 名已确诊为良性前列腺增生症(根据 ICD-10 诊断为 N40)的 LUTS 患者,并对其进行了所有阶段的检查。所有患者均接受了坦索罗辛 0.4 毫克/天的单药治疗,疗程至少 8 周。评估治疗效果的方法包括生活质量定义的 IPSS 问卷调查、前列腺超声波检查(测定前列腺体积和残余尿量)以及尿流率测定。在治疗开始后的 2 周、4 周和 8 周进行对照。测定了患者体内CYP3A4(*1B、*22)和CYP3A5*3的多态性标记;采用高效液相色谱法测定血浆中的药物浓度和尿液中的皮质醇及其代谢物6-beta-羟基皮质醇水平,以评估CYP3A的表型活性。在研究的患者样本中,没有发现 CYP3A 表型(由 CYP3A4 和 CYP3A5 基因型定义)与坦索罗辛疗效和安全性评估的临床参数之间有统计学意义的关联(P >0.05)。CYP3A4*1B、CYP3A4*22、CYP3A5*3的单个变体也获得了类似的数据(P>0.05)。通过比较研究样本中患者与 CYP3A4 和 CYP3A5 基因变异携带者的坦索罗辛残余平衡浓度值,没有发现 CYP3A 表型、CYP3A4*1B(p=0.57)、CYP3A4*22(p=0.37)和 CYP3A5*3(p=0.76)变异携带者与非携带者之间存在显著差异。尿液中 6-beta-hydroxycortisol / cortisol 的代谢比率与 CYP3A 表型(由 CYP3A4 和 CYP3A5 基因变异的基因型组合编码)之间没有关联(p >0.05)。CYP3A4*1B、CYP3A4*22和CYP3A5*3变体的携带、通过尿液中该同工酶内源性底物及其代谢物含量评估的CYP3A活性、药物血浆浓度水平与坦索罗辛的疗效和安全性之间可能存在的关联尚未得到证实。CYP3A4 和 CYP3A5 基因多态性对坦索罗辛治疗临床参数的影响还需要进一步研究。
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