title: Structural requirements of bile acid transporters: C-3 and C-7 modifications of steroidal hydroxyl groups.
abstract: The apical sodium dependent bile acid transporter (ASBT) and sodium-taurocholate cotransporting polypeptide (NTCP) are potential prodrug targets, but the structural requirements for these transporters are incompletely defined. The objective of this study was to evaluate the effect of C-3 and C-7 substitution on bile acid interaction with these bile acid transporters. Nineteen bile acid analogs were tested against ASBT and NTCP for binding, as well as translocation. Results indicated that ASBT and NTCP accommodated a wide range of substituents for binding, but all major C-7 modifications resulted in analogs that did not demonstrate active uptake by either ASBT or NTCP. A C-3 modification that was not tolerated at C-7 still afforded translocation via ASBT and NTCP, confirming the relative unacceptability of C-7 modification. Both ASBT and NTCP demonstrated a generally similar binding potency. Results suggest that drug conjugation to the C-3 hydroxyl group, rather than C-7, has potential to lead to a successful prodrug targeting ASBT and NTCP.
authors.affiliation: Univerisity of Maryland, School of Pharmacy, Baltimore, MD 21201, USA.
authors.forename: Vidula
authors.initials: V
authors.lastname: Kolhatkar
authors.forename: James E
authors.initials: JE
authors.lastname: Polli
mesh_terms: D001647:Bile Acids and Salts / Q000737:chemistry* / Q000493:pharmacokinetics*; D001692:Biological Transport; D002460:Cell Line; D016503:Drug Delivery Systems; D006801:Humans; D007082:Ileum / Q000378:metabolism; D029363:Organic Anion Transporters, Sodium-Dependent / Q000737:chemistry / Q000378:metabolism*; D011355:Prodrugs / Q000378:metabolism; D021281:Quantitative Structure-Activity Relationship; D027981:Symporters / Q000737:chemistry / Q000378:metabolism*; D013656:Taurocholic Acid / Q000737:chemistry / Q000378:metabolism
chemical_list: D001647:Bile Acids and Salts; D029363:Organic Anion Transporters, Sodium-Dependent; D011355:Prodrugs; D027981:Symporters; C071908:sodium-bile acid cotransporter; D013656:Taurocholic Acid