Category: Preclinical Development
Purpose: Enterohepatic recycle (EHR) is an important drug disposition process. Metabolites excreted into bile are considered to be generated in hepatocyte. However, our recent study indicates that non-hepatic metabolism (like intestinal metabolism) has the same impact in the EHR process. Some compounds could be metabolized before enter liver and excreted into bile after uptaken by hepatocyte. Without any hepatic metabolism, the compounds would go through EHR as well. The purpose of the study is to elucidate the mechanism of hepatic uptake of these compounds and the structure related activity.
Methods: An in situ portal vein infusion model was established to study the mechanism. Hepatic portal vein and bile duct were catheterized with tubes. Different flavonoid glucuronides and their aglycones were infused through portal vein catheterization at the rate of 2 ml/hr. The infusion lasted for 2.5 hours. Bile and blood (from tail vein) were collected every 0.5 hour. The RE% (recycling efficiency) of individual flavonoid glucuronide was calculated. For one of the flavonoid (wogonoside), 5 different concentrations were infused through portal vein and RE% was calculated. Recycle inhibition study was also conducted by adding uptake transporter inhibitors with selected flavonoid glucuronides. Wogonin and baicalein was further utilized to conduct a multiple-dose PK study to confirm the recycle properties.
Results: Different flavonoid glucuronides had different RE%. The RE% of wogonoside was higher than 90% while the RE% of baicalin was lower than 10%. Compared to their glucuronides (at 10 uM, 2 ml/hr), the infused aglycones (at 10 uM, 2 ml/hr) had lower RE%. When infused with OATP inhibitors, the RE% of wogonoside decreased 50%. Wogonin showed a higher AUC than baicalein in the form of glucuronide, which indicated that the efficient recycle of wogonoside increased the AUC of wogonoside.
Conclusion: In conclusion, the recycle of the flavonoid glucuronide indicated a concentration dependent process. The recycle could be inhibited by OATPs inhibitors, which indicate that OATP transporters play the major role in the recycle process. Since different flavonoid glucuronides had different RE%, structure has significant impact on recycling efficiency of flavonoids. The recycle properties we observed in infusion model had consistent impact on in vivo study.
Song Gao– Assistant Professor, Texas Southern University, Houston, Texas
Taijun Yin– Lab Manager, University of Houston, Houston, Texas
Min Zeng– Visiting Scholar, University of Houston, Houston, Texas
Jiong Liu– Visiting Scholar, University of Houston, Houston, Texas
Lei Zhou– Houston, Texas
Lu Wang– Student, University of Houston, Houston, Texas
Ming Hu– Professor of Pharmaceutics, University of Houston, Houston, Texas