Ileal bile acid transporter inhibition, CYP7A1 induction, and antilipemic action of 264W94

W94 was designed to inhibit the ileal bile acid transporter (IBAT). Evaluated in vitro, 264W94 dose- dependently inhibited sodium-dependent uptake of 10 � M ( 3 H)taurocholic acid (TC) by rat and monkey brush border membrane vesicles with IC 50 s of 0.24 � M and 0.41 � M, and had a competitive profile with K i of 0.2 � M against TC in Chinese hamster ovary cells expressing human IBAT. In dis- tal ileum in situ, 1-10 � M of 264W94 rapidly decreased up- take of 3mM TC by 24-39%, with corresponding decreases in biliary recovery. In rats and mice in vivo, oral 264W94 de- creased absorption of TC analog, 23,25- 75 Se-homocholic acid taurine ( 75 SeHCAT; quantitated in feces), with ED 30 of