Abstract：
:Human sodium taurocholate co-transporting polypeptide (NTCP) is the main bile acid uptake transporter in the liver with the capability to translocate xenobiotics. While its inhibitor requirements have been recently characterized, its substrate requirements have not. The objectives of this study were (a) to elucidate NTCP substrate requirements using native bile acids and bile acid analogs, (b) to develop the first pharmacophore for NTCP substrates and compare it with the inhibitor pharmacophores, and (c) to identify additional NTCP novel substrates. Thus, 18 native bile acids and two bile acid conjugates were initially assessed for NTCP inhibition and/or uptake, which suggested a role of hydroxyl pattern and steric interaction in NTCP binding and translocation. A common feature pharmacophore for NTCP substrate uptake was developed, using 14 native bile acids and bile acid conjugates, yielding a model which featured three hydrophobes, one hydrogen bond donor, one negative ionizable feature and three excluded volumes. This model was used to search a database of FDA approved drugs and retrieved the majority of the known NTCP substrates. Among the retrieved drugs, irbesartan and losartan were identified as novel NTCP substrates, suggesting a potential role of NTCP in drug disposition.
journal_name
Int J Pharmjournal_title
International journal of pharmaceuticsauthors
Dong Z,Ekins S,Polli JEdoi
10.1016/j.ijpharm.2014.11.022subject
Has Abstractpub_date
2015-01-15 00:00:00pages
88-95issue
1eissn
0378-5173issn
1873-3476pii
S0378-5173(14)00825-4journal_volume
478pub_type
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