Tabata K, Yamaoka K, Fukuyama T, Nakagawa T
Faculty of Pharmaceutical Science, Kyoto University, Japan.
Pharm Res. 1995 Jun;12(6):880-3. doi: 10.1023/a:1016217221977.
We evaluated the first-pass effects in vivo by the intestine and liver during enterophepatic circulation (EHC) by simultaneously measuring the portal and venous plasma concentrations of the rat.
The venous and upper portal blood vessels were cannulated through the jugular and the pyloric veins, respectively, to obtain simultaneously blood samples from both sites. After diclofenac was injected as a bolus through the jugular vein, the concentrations of diclofenac in the portal and jugular veins were measured at time intervals. The absorption rate from the intestinal tract into the portal system was determined using the portal-venous difference in plasma concentrations of diclofenac, considering 40% partitioning of diclofenac into erythrocytes.
After one hour, the plasma concentration in the portal vein was always higher than that in the jugular vein in awakening rats with intact EHC (portal-venous blood concentration difference). No portal-venous difference was observed in awakening rats with bile-duct cannulation. Therefore, it was concluded that this portal-venous concentration difference was not due to the hepatic clearance but to diclofenac reabsorption from the intestinal tract.
Approximately 40% of the dose of diclofenac was reabsorbed over 8 hours from the intestinal tract into the portal system. By comparing the reabsorbed amounts in the portal system and in the systemic circulation, the hepatic extraction ratio in vivo (FH) of diclofenac was estimated to be 63%.
通过同时测量大鼠门静脉和静脉血浆浓度，评估肠肝循环（EHC）过程中肠道和肝脏在体内的首过效应。
分别通过颈静脉和幽门静脉插管至静脉和上门静脉血管，以同时从两个部位采集血样。经颈静脉快速推注双氯芬酸后，定期测量门静脉和颈静脉中双氯芬酸的浓度。考虑到双氯芬酸40%分布于红细胞中，利用双氯芬酸血浆浓度的门静脉-静脉差值来确定从肠道吸收进入门静脉系统的速率。
1小时后，在具有完整EHC的清醒大鼠中，门静脉中的血浆浓度始终高于颈静脉中的血浆浓度（门静脉-静脉血浓度差值）。在胆管插管的清醒大鼠中未观察到门静脉-静脉差值。因此，得出结论，这种门静脉-静脉浓度差值并非由于肝脏清除，而是由于双氯芬酸从肠道重吸收。
双氯芬酸剂量的约40%在8小时内从肠道重吸收进入门静脉系统。通过比较门静脉系统和体循环中的重吸收量，双氯芬酸在体内的肝提取率（FH）估计为63%。
