Pharmacokinetics and disposition of silodosin (KMD-3213)
Pharmacokinetics and disposition of silodosin (KMD-3213)
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DOI：
10.1248/yakushi.126.237
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发表时间：
2006-03-01
影响因子：
0.3
通讯作者：
Midgley, I
中科院分区：
文献类型：
--
作者：
Matsubara, Y;Kanazawa, T;Midgley, I
雄性大鼠、雄性犬和健康男性志愿者单次口服西洛多辛后，C-max在约2小时内出现，表明吸收迅速。在大鼠和犬中的消除半衰期约为2 It，但在人体中为4.7 h（禁食）和6.0 h（非禁食）。大鼠、犬和人的绝对生物利用度值分别约为9%、25%和32%。在大鼠和犬中，总血液清除率几乎等于肝血流量，但在人体中较低（20%），表明肝清除率存在较大的种属差异。在每个物种中，表观分布体积超过了总身体水的体积。雄性大鼠经口给予C-14-西洛多辛后，放射性迅速且广泛分布至大部分组织。在胃肠道外，肝脏和肾脏中的浓度最高，脑组织中的浓度较低。西洛多辛的体外血浆蛋白结合率在大鼠和犬中约为80%，在人中约为95.6%，α（1）-酸性糖蛋白（AGP）有助于结合特征。发现赛洛多辛是CYP 3A 4和P-糖蛋白的双重底物。在人血浆中，发现UDP-葡萄糖醛酸基转移酶（UGT; UGT 2B 7）和乙醇/醛脱氢酶（ADH/ALDH）产生的两种主要代谢产物，但在大鼠或犬血浆中未检测到葡糖苷酸结合物。大鼠、犬和人单次经口给予C-14-西洛多辛后，放射性的尿排泄率为15- 34%，原型西洛多辛的尿排泄率低于4%。放射性主要通过粪便排泄。
After a single oral dose of silodosin in male rats, male dogs and healthy human male volunteers, C-max occurred within about 2 h, indicating rapid absorption. The elimination half-life was about 2 It in rat and dog, but 4.7 h (fasted) and 6.0 h (non-fasted) in humans. Absolute bioavailability values in rat, dog, and human were about 9, 25 and 32%, respectively. In rat and dog, total blood clearance was almost equivalent to the hepatic blood flow, but that in human was low (20%.), demonstrating a large species difference in hepatic clearance. In each species, the apparent volume of distribution exceeded the volume of total body water. After an oral dose of C-14-silodosin to male rats, radioactivity was rapidly and widely distributed to most tissues. The highest concentrations Outside the gastrointestinal tract were found in liver and kidney, with only low concentrations in brain tissues. The in vitro plasma protein binding of silodosin was about 80% in rat and dog, and 95.6% in humans, with alpha(1)-acid glycoprotein (AGP) contributing to the binding- profile. Silodosin was found to be a dual substrate for CYP3A4 and p-glycoprotein. In human plasma, two major metabolites generated by UDP-glucuronosyltransferase (UGT; UGT2B7) and alcohol/aldehyde dehydrogenase (ADH/ALDH) were found, but no glucuronide conjugates were detected in rat or dog plasma. After a single oral dose of C-14-Silodosin in rat, dog, and human, the urinary excretion of radioactivity was 15-34%, with that of unchanged silodosin being-less than 4%. The radioactivity was predominantly excreted via the feces.