title: Ileal bile acid transporter inhibition, CYP7A1 induction, and antilipemic action of 264W94.
abstract: 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.
authors.affiliation: Departments of Information Analysis, GlaxoSmithKline Research and Development, Research Triangle Park, NC 27709, USA.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Root
authors.forename: Chari D
authors.initials: CD
authors.lastname: Smith
authors.forename: Scott S
authors.initials: SS
authors.lastname: Sundseth
authors.forename: Heather M
authors.initials: HM
authors.lastname: Pink
authors.forename: Joan G
authors.initials: JG
authors.lastname: Wilson
authors.forename: Michael C
authors.initials: MC
authors.lastname: Lewis
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D001647:Bile Acids and Salts / Q000378:metabolism; D016466:CHO Cells; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D002790:Cholesterol 7-alpha-Hydroxylase / Q000096:biosynthesis*; D006224:Cricetinae; D004790:Enzyme Induction; D005243:Feces; D006913:Hydroxysteroid Dehydrogenases; D007082:Ileum / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D007408:Intestinal Absorption; D008297:Male; D008562:Membrane Glycoproteins; D008871:Microvilli / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013841:Thiazepines / Q000494:pharmacology*; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific)
chemical_list: D000924:Anticholesteremic Agents; D001647:Bile Acids and Salts; D002352:Carrier Proteins; D002790:Cholesterol 7-alpha-Hydroxylase; D006913:Hydroxysteroid Dehydrogenases; D008562:Membrane Glycoproteins; D013841:Thiazepines; C119986:264W 94; C037643:bile acid binding proteins; C435496:AKR1C2 protein, human; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific)