INHIBITION OF ILEAL SODIUM-DEPENDENT BILE-ACID TRANSPORT BY 2164U90

Inhibition of the ileal bile acid active transport system, previously shown to be mechanism underlying the hypocholesterolemic activity of 2 164U90 in rodents, was further characterized in isolated intestinal pr eparations from three species. 2164U90 inhibited sodium-dependent tran sport of taurocholic acid by Caco-2 cells and by monkey and human ilea l brush border membrane vesicles in a concentration-dependent manner w ith IC(50)s Of 7 mu M, 5 mu M, and 2 mu M, respectively. In rat ileal brush border membrane vesicles, 2164U90 was a competitive inhibitor of sodium-dependent taurocholic acid uptake with an estimated K-i of 1.8 +/- 0.2 mu M In anesthetized rats, 5 mu M 2164U90 placed in the isola ted distal ileum with 3 mM [H-3]taurocholic acid decreased ileal uptak e, transport into the bile, and transport rate of taurocholic acid by 31-35%. Stereospecificity of inhibition by 2164U90 was demonstrated by the relative inactivity of three other possible stereoisomers in rat ileal sacs and brush border membrane vesicles. 2164U90 did not inhibit sodium-dependent glucose transport by monkey jejunal brush border mem brane vesicles, indicating that 2164U90 may be specific for the bile a cid transporter. These results suggest that 2164U90 is a potent, selec tive, stereospecific, competitive inhibitor of the sodium-dependent bi le acid transporter in the ileal mucosal cell brush border membrane.