Sung Jong-Hyuk, Hong Soon-Sun, Ahn Sung-Hoon, Li Hong, Seo Seung-Yong, Park Chul-Hong, Park Byung-Soon, Chung Suk-Jae
College of Pharmacy, Seoul National University, Seoul 151-742, Korea.
J Pharm Pharmacol. 2006 May;58(5):643-9. doi: 10.1211/jpp.58.5.0009.
The mechanism associated with the increased bioavailability of tacrine as a result of a 24-h period of fasting was examined in rats. The AUC value for tacrine after the fasting was 52% higher compared with normal feeding when 4 mg kg(-1) of tacrine was orally administered, but the value for velnacrine, a hydroxylated metabolite of tacrine, was reduced by 10%. The relative metabolic ratio of tacrine in urinary excretion (Au(tacrine) divided by Au(velnacrine)) was lower in fasted rats compared with normally fed rats. This clearly shows that metabolism of tacrine is reduced with 24-h fasting after oral administration. Altered intestinal permeation in the fasting state was hypothesized, and the transport of tacrine across the rat intestine was studied. When a fasted intestine was mounted in an Ussing chamber, the mucosal-to-serosal permeability of tacrine was increased to double that for a fed rat intestine. To examine the effect of absorption rate on the hepatic metabolism of tacrine, a direct pyloric vein infusion study was carried out. Compared with an infusion of tacrine for 5 min, a slow infusion of tacrine over a period of 30 or 60 min increased the hepatic metabolism of tacrine and decreased its systemic clearance in rats. Collectively, these results suggest that rapid transport across the intestine aids tacrine in avoiding hepatic first-pass metabolism and enhances its bioavailability in fasted rats. From these findings, we conclude that both oral administration before a meal and a reduction in the dose might be recommended in tacrine therapy considering the serious hepatotoxicity of tacrine in clinical use.
在大鼠中研究了禁食24小时导致他克林生物利用度增加的相关机制。口服给予4mg/kg他克林后，禁食后的他克林AUC值比正常喂食时高52%，但其羟基化代谢物维拉克林的值降低了10%。与正常喂食的大鼠相比，禁食大鼠尿液排泄中他克林的相对代谢率（他克林的Au除以维拉克林的Au）较低。这清楚地表明，口服给药后禁食24小时会降低他克林的代谢。推测禁食状态下肠道渗透发生改变，并研究了他克林在大鼠肠道中的转运。当将禁食的肠道安装在Ussing室中时，他克林的黏膜到浆膜的渗透率增加到喂食大鼠肠道的两倍。为了研究吸收速率对他克林肝脏代谢的影响，进行了直接幽门静脉输注研究。与输注他克林5分钟相比，在30或60分钟内缓慢输注他克林会增加大鼠肝脏对他克林的代谢并降低其全身清除率。总体而言，这些结果表明，在禁食大鼠中，快速通过肠道转运有助于他克林避免肝脏首过代谢并提高其生物利用度。根据这些发现，考虑到他克林在临床使用中的严重肝毒性，我们得出结论，在他克林治疗中可能建议饭前口服给药并减少剂量。
