A substrate pharmacophore for the human sodium taurocholate co-transporting polypeptide

Area of Science:

• Hepatology and Drug Transport
• Biochemistry and Molecular Biology

Background:

• Human sodium taurocholate co-transporting polypeptide (NTCP) is the primary hepatic transporter for bile acid uptake.
• NTCP also facilitates the translocation of various xenobiotics, but its substrate requirements remain largely uncharacterized.
• Understanding NTCP substrate specificity is crucial for predicting drug interactions and disposition.

Purpose of the Study:

• To elucidate the substrate requirements of the human NTCP transporter.
• To develop the first pharmacophore model for NTCP substrates.
• To identify novel NTCP substrates among FDA-approved drugs.

Main Methods:

• Assessment of 18 native bile acids and two bile acid conjugates for NTCP inhibition and/or uptake.
• Development of a common feature pharmacophore model for NTCP substrates using bile acids and conjugates.
• Database searching of FDA-approved drugs using the developed pharmacophore model.

Main Results:

• Bile acid hydroxyl pattern and steric interactions significantly influence NTCP binding and translocation.
• A pharmacophore model for NTCP substrates was developed, featuring specific hydrophobic, hydrogen bond donor, negative ionizable features, and excluded volumes.
• The model successfully identified known NTCP substrates and revealed irbesartan and losartan as novel substrates.

Conclusions:

• The substrate requirements of NTCP have been elucidated through the development of a predictive pharmacophore model.
• Irbesartan and losartan are identified as novel substrates for NTCP, highlighting its role in the disposition of certain drugs.
• This research provides valuable insights into NTCP-mediated drug transport and potential drug-drug interactions.