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Journal of Lipid Research, Vol. 43, 1320-1330, August 2002
Copyright © 2002 by Lipid Research, Inc.

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

Carolyn Root^*, Chari D. Smith, Scott S. Sundseth, Heather M. Pink^**, Joan G. Wilson and Michael C. Lewis^1,

^* Departments of Information Analysis, GlaxoSmithKline Research and Development, Research Triangle Park, NC 27709
Biochemical & Analytical Pharmacology, GlaxoSmithKline Research and Development, Research Triangle Park, NC 27709
Medical Genetics, GlaxoSmithKline Research and Development, Research Triangle Park, NC 27709
^** Molecular Pharmacology, GlaxoSmithKline Research and Development, Research Triangle Park, NC 27709
Metabolic Diseases, GlaxoSmithKline Research and Development, Research Triangle Park, NC 27709

¹ To whom correspondence should be addressed. e-mail: MCL38459{at}gsk.com

264W94 was designed to inhibit the ileal bile acid transporter (IBAT). Evaluated in vitro, 264W94 dose-dependently inhibited sodium-dependent uptake of 10 µM [³H]taurocholic acid (TC) by rat and monkey brush border membrane vesicles with IC₅₀s of 0.24 µM and 0.41 µM, and had a competitive profile with K_i of 0.2 µM against TC in Chinese hamster ovary cells expressing human IBAT. In distal ileum in situ, 1–10 µM 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, 23,25-⁷⁵Se-homocholic acid taurine (⁷⁵SeHCAT; quantitated in feces), with ED₃₀ of 0.02 mg/kg bid. ⁷⁵SeHCAT traced through the GI-tract revealed that peak (97%) inhibition of ⁷⁵SeHCAT 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 7-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.

Abbreviations: BAS, bile acid sequestrants; BBMV, brush border membrane vesicles; CHO, Chinese hamster ovary; EHC, enterohepatic circulation; IBAT, ileal bile acid transporter; PIB, partial ileal bypass; ⁷⁵SeHCAT, 23,25-⁷⁵Se-homocholic acid taurine; TC, taurocholic acid

Supplementary key words CAS RN 178961-24-5 • human ileal apical sodium-dependent bile acid co-transporter • brush border membrane vesicles • cholesterol 7-monooxygenase • hypocholesterolemic agents • ⁷⁵Se-homocholic acid taurine • taurocholic acid • monkeys • mice • rats

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