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 2164U90 in rodents, was further characterized in isolated intestinal preparations from three species. 2164U90 inhibited sodium-dependent transport of taurocholic acid by Caco-2 cells and by monkey and human ileal brush border membrane vesicles in a concentration-dependent manner with IC50s of 7 microM, 5 microM, and 2 microM, respectively. In rat ileal brush border membrane vesicles, 2164U90 was a competitive inhibitor of sodium-dependent taurocholic acid uptake with an estimated Ki of 1.8 +/- 0.2 microM. In anesthetized rats, 5 microM 2164U90 placed in the isolated distal ileum with 3 mM [3H]taurocholic acid decreased ileal uptake, 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 membrane vesicles, indicating that 2164U90 may be specific for the bile acid transporter. These results suggest that 2164U90 is a potent, selective, stereospecific, competitive inhibitor of the sodium-dependent bile acid transporter in the ileal mucosal cell brush border membrane.