The Physicochemical Properties, in Vitro Metabolism and Pharmacokinetics of a Novel Ester Prodrug of EXP3174

详细信息    查看全文

• 作者：Yi-Dong Yan ; Han-Kyung Kim ; Ki-Heon Seo ; Won Seok Lee ; Gwan-Sun Lee ; Jong-Soo Woo ; Chul-Soon Yong ; Han-Gon Choi
• 刊名：Molecular Pharmaceutics
• 出版年：2010
• 出版时间：December 6, 2010
• 年：2010
• 卷：7
• 期：6
• 页码：2132-2140
• 全文大小：266K
• 年卷期：v.7,no.6(December 6, 2010)
• ISSN：1543-8392

文摘

EXP3174 is the major active metabolite of losartan, a drug currently widely used for the treatment of cardiovascular diseases. This study was designed to evaluate the physicochemical properties of EXP3174-pivoxil (a novel synthesized prodrug of EXP3174) and characterize its metabolism, regional intestinal absorption and pharmacokinetics by in vitro and in vivo studies. An in vitro metabolism study was conducted in liver and intestinal S9 fractions from different species including rat, dog and human. In vivo absorption was investigated following regional intestinal dosing in rats, and the pharmacokinetics was determined using rats after a single oral administration. EXP3174-pivoxil exhibited predictable stability in the aqueous solution within a pH range of 1.2−9.0 as well as in the solid form of powder. An in vitro metabolism study revealed that EXP3174-pivoxil was rapidly and efficiently converted into EXP3174 by enzymatic hydrolysis. The dose administered into the duodenum and jejunum resulted in higher values for the AUC_0−24h and C_max than those following ileum dosing (p < 0.05). Furthermore, the AUC_0−24h and C_max values for EXP3174 increased in a dose-dependent manner as dose increased from 0.5 to 5 mg/kg. A comparable AUC_0−24h, shortened T_max and a significant increase in the plasma C_max of EXP3174 were observed following oral administration of EXP3174-pivoxil (as EXP3174, 1 mg/kg) compared with those of losartan (as EXP3174, 5 mg/kg) in rats, suggesting faster absorption and a 5-fold enhancement in the bioavailability of EXP3174. These results suggest that EXP3174-pivoxil may serve as a more effective drug even at lower clinical doses by exhibiting increased bioavailability and faster therapeutic response, compared with losartan.

Keywords:

Prodrug; EXP3174; physicochemical property; metabolism; pharmacokinetics; oral bioavailability