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

264W94 was designed to inhibit the ileal bile acid transporter (IBAT). Evaluated in vitro, 264W94 dose-dependently inhibited sodium-dependent uptake of 10 micro M [(3)H]taurocholic acid (TC) by rat and monkey brush border membrane vesicles with IC(50)s of 0.24 micro M and 0.41 micro M, and had a competitive profile with K(i) of 0.2 micro M against TC in Chinese hamster ovary cells expressing human IBAT. In distal ileum in situ, 1-10 micro M of 264W94 rapidly decreased uptake of 3mM TC by 24-39%, with corresponding decreases in biliary recovery. In rats and mice in vivo, oral 264W94 decreased absorption of TC analog, 23,25-(75)Se-homocholic acid taurine ((75)SeHCAT; quantitated in feces), with ED(30) of 0.02 mg/kg bid. (75)SeHCAT traced through the GI-tract revealed that peak (97%) inhibition of (75)SeHCAT absorption by the distal quarter of small intestine occurred at 4 h after single dose of 264W94 (0.1 mg/kg). Inhibition of IBAT by 264W94 in rats was associated with compensatory, same-day, 4-fold induction of hepatic Cholesterol 7alpha-hydroxylase (CYP7A1) activity, exhibiting normal diurnal fluctuation for 3 days of dosing. In diet induced hypercholesterolemic rats, 264W94 (0.03-1.0 mg/kg bid) dose-dependently reduced serum LDL+VLDL Cholesterol up to 61%. In conclusion, 264W94 is a potent new Cholesterol lowering agent that acts through inhibition of IBAT and exhibits activity in a human model.