Department of Life and Nanopharmaceutical Sciences, Kyung Hee University, Seoul, 130-701, Korea.
J Pharm Pharm Sci. 2012;15(4):528-37. doi: 10.18433/j35p59.
Hyperlipidemia is associated with an increased risk of erectile dysfunction. In this study, we investigated the effects of hyperlipidemia on the pharmacokinetics of tadalafil, a novel therapeutic agent for erectile dysfunction, in rats with experimental hyperlipidemia.
Tadalafil (1 mg/kg) was administered to control rats and rats with poloxamer-407-induced hyperlipidemia (1 g/kg, i.p.). In addition, we performed in vitro studies to determine the hepatic metabolism in S9 fractions, intestinal absorption, and plasma protein binding.
Hyperlipidemia dramatically increased tadalafil's the total area under the plasma concentration-time curve from time 0 to infinity after intravenous (2.09-fold) and oral (11.9-fold) administration, and decreased total body clearance (0.537-fold) and apparent volume of distribution at the steady state (0.438-fold) after intravenous administration of tadalafil. Further, we observed decreased in vitro hepatic S9 metabolism, intestinal first-pass metabolism, and unbound fraction of tadalafil.
The alterations in the pharmacokinetics of tadalafil observed in rats with poloxamer 407-induced hyperlipidemia may be attributable to a decrease in hepatic and intestinal metabolism and unbound fraction of tadalafil in the plasma. These findings have potential therapeutic implications for predicting the pharmacokinetic responses of humans to hyperlipidemia. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.
高脂血症与勃起功能障碍的风险增加有关。在这项研究中，我们研究了实验性高脂血症大鼠中海泊利单抗 407 诱导的高脂血症对西地那非药代动力学的影响，西地那非是一种新型勃起功能障碍治疗药物。
给予对照组大鼠和泊洛沙姆 407 诱导的高脂血症大鼠（1g/kg，ip）西地那非（1mg/kg）。此外，我们进行了体外研究，以确定 S9 级分中的肝代谢、肠吸收和血浆蛋白结合。
高脂血症显著增加了西地那非静脉（2.09 倍）和口服（11.9 倍）给药后从 0 到无穷大的血浆浓度-时间曲线下总面积，并降低了总清除率（0.537 倍）和静脉内给予西地那非后的稳态表观分布容积（0.438 倍）。此外，我们观察到西地那非在体外的肝 S9 代谢、肠首过代谢和未结合分数降低。
泊洛沙姆 407 诱导的高脂血症大鼠中西地那非药代动力学的改变可能归因于肝和肠代谢以及血浆中西地那非未结合分数的降低。这些发现对预测人类对高脂血症的药代动力学反应具有潜在的治疗意义。本文接受 POST-PUBLICATION REVIEW。注册读者（见“读者须知”）可通过点击问题内容页面上的 ABSTRACT 进行评论。
