Effects of 2164U90 on ilea and serum ch and mice

U90, ((3R,5R)-tram-3-butyl-3-ethyl-2,3,4,5-tetra- hydro-5-pheny1-1,4-benzothiazepine 1,l-dioxide), was found to be a potent inhibitor of the ileal bile acid active transport system. In vitro, 2164U90 decreased uptake and active transport of taurocholic acid by rat everted ileal sacs with IC50s of 4.0 pM and 1.5 p~, respectively. In vivo, 2164U90 produced dose- dependent increases in 23,25-75Se-labeled homocholic acid tau- rine (SeHCAT) fecal excretion in rats and mice at doses of 3-30 mg/kg and 1-10 mg/kg, respectively. In rats, 30 mg/kg 2164U90 was equivalent to 500 mg/kg cholestyramine. Two days oral administration of 10 mg/kg 2164U90 to rats decreased the bile concentrations of total bile acids 42%, orally administered (3H)taurocholic acid ((3H)TC) 82%, and cholesterol 35%. Cholestyramine (500 mg/kg) had effects similar to 2164U90 on total bile acid and orally administered ( 3H)TC concentrations but had no effect on biliary cholesterol. The hypocholesterolemic activity of 2164U90 was determined in cholesterol-cholic acid-fed rats and cholesterol-cholic acid-coconut oil-fed mice. 2164U90 inhibited the dietary-induced increase in dextran sulfate- precipitable lipoprotein cholesterol (VLDL + LDL) at doses comparable to doses needed to increase the fecal excretion of bile acids. These data indicate that 2164U90 decreases bile acid absorption by inhibiting the ileal bile acid active transport sys- tem, resulting in hypocholesterolemic activity- Lewis, M. C., L. E. Brieaddy, and C. Root. Effects of 2164U90 on ileal bile acid absorption and serum cholesterol in rats and mice. J. Lipid or increas- ing the conversion of cholesterol to bile acids with bile acid sequestrants. Bile acids are synthesized in the liver and secreted into the small intestine where they facilitate fat and cholesterol absorption. More than 90% of the bile acids are reab- sorbed either by passive diffusion along the entire intes- tine or actively at the terminal ileum. The small amount of bile acids not reabsorbed is excreted into feces and replenished by hepatic synthesis from cholesterol. De- creasing the enterohepatic flux of bile acids increases bile acid synthesis by induction of cholesterol 'la-hydroxylase, the rate-limiting enzyme in bile acid synthesis. Bile acid