The Influence of UGT2B7, UGT1A8, MDR1, ALDH, ADH, CYP3A4 and CYP3A5 Genetic Polymorphisms on the Pharmacokinetics of Silodosin in Healthy Chinese Volunteers
The Influence of UGT2B7, UGT1A8, MDR1, ALDH, ADH, CYP3A4 and CYP3A5 Genetic Polymorphisms on the Pharmacokinetics of Silodosin in Healthy Chinese Volunteers
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UGT2B7、UGT1A8、MDR1、ALDH、ADH、CYP3A4和CYP3A5基因多态性对西洛多辛在中国健康志愿者体内药代动力学的影响
DOI：
10.2133/dmpk.dmpk-12-rg-106
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发表时间：
2013-06-25
影响因子：
2.1
通讯作者：
Zhou, Ying
中科院分区：
文献类型：
--
作者：
Wang, Zining;Xiang, Qian;Zhou, Ying
背景资料：Silodosin（KMD-3213）是一种高选择性α 1a-肾上腺素能受体拮抗剂，在日本（2006年）、美国（2008年）和中国（2011年）获批用于治疗良性前列腺增生。西洛多辛是CYP 3A和P-糖蛋白的双重底物，血浆中通过UDP-葡萄糖醛酸转移酶（UGT）和乙醇/醛脱氢酶产生两种主要代谢产物。目的：研究基因多态性对中国健康男性单剂量口服西洛多辛药代动力学的影响。方法：在口服4 mg西洛多辛之前和之后的预定时间间隔从受试者（n = 31）收集血液样品。使用经验证的LC/MS/MS方法定量血浆西洛多辛浓度。评估了每例受试者的血浆西洛多辛浓度、其药代动力学参数、多态性等位基因（UGT 2B 7、UGT 1A 8、MDR 1、ALDH、ADH、CYP 3A 4和CYP 3A 5）以及与西洛多辛代谢相关的其他酶之间的关系。结果如下：与UGT 2B 7 *1/*1受试者相比，UGT 2B 7 *1/*2和 *2/*2受试者的终末t（1/2）分别延长27.1%和22.7%，AUC（0-无穷大）分别增加37.9%和25.2%，西洛多辛代谢减慢，西洛多辛暴露增加。西洛多辛T.受CYP 3A 5影响（p < 0.05），与 *1/*3或 *3/*3多态性受试者相比，CYP 3A 5 *1/*1多态性受试者达到C-max的时间较慢。C-max受到CYP 3A 4的影响（p < 0.05），与 *1/*1和 *1/* 18 B的受试者相比，CYP 3A 4 * 18 B/* 18 B的受试者的C-max较低。UGT 2B 7可能在西洛多辛代谢中观察到的变异性中发挥关键作用。
Background: Silodosin (KMD-3213), a highly selective alpha 1a-adrenergic receptor antagonist, was approved in Japan (2006), the United States of America (2008), and China (2011) for benign prostatic hyperplasia. Silodosin was a dual substrate for CYP3A and P-glycoprotein, and two main metabolites were generated in plasma by UDP-glucuronosyltransferase (UGT) and alcohol/aldehyde dehydrogenase. Aim: To examine the effect of genetic polymorphisms on silodosin pharmacokinetics in healthy male Chinese subjects after a single oral dose. Methods: Blood samples were collected from subjects (n = 31) at scheduled time intervals before and after an oral administration of 4 mg silodosin. A validated LC/MS/MS method was used to quantify the plasma silodosin concentration. The relationship between plasma silodosin concentration, its pharmacokinetic parameters, polymorphic alleles (UGT2B7, UGT1A8, MDR1, ALDH, ADH, CYP3A4, and CYP3A5), and other enzymes related to silodosin metabolism were assessed for each subject. Results: Subjects with UGT2B7*1/*2 and *2/*2 had a 27.1% and 22.7% longer terminal t(1/2) (respectively), 37.9% and 25.2% larger AUC(0-infinity) (respectively), slower silodosin metabolism, and increased silodosin exposure, when compared to the subjects with UGT2B7*1/*1. The silodosin T. was affected by CYP3A5 (p < 0.05) with a slower time to reach C-max for subjects with the CYP3A5*1/*1 polymorphism when compared to those with the *1/*3 or *3/*3 polymorphisms. The C-max was affected by CYP3A4 (p < 0.05) with a lower C-max for subject with the CYP3A4*18B/*18B compared to those with the *1/*1 and *1/*18B. UGT2B7 may play a key role in the variability observed in silodosin metabolism.