EFFECTS OF 2164U90 ON ILEAL BILE-ACID ABSORPTION AND SERUM-CHOLESTEROL IN RATS AND MICE

2164U90, )-trans-3-butyl-3-ethyl-2,3,4,5-hydro-5-phenyl-1,4 -benzothia zepine 1,1-dioxide], was found to be a potent inhibitor of the ileal b ile acid active transport system. In vitro, 2164U90 decreased uptake a nd active transport of taurocholic acid by rat everted ileal sacs with IC(50)s Of 4.0 mu M and 1.5 mu M, respectively. In vivo, 2164U90 prod uced dose-dependent increases in 23,25-Se-75-labeled homocholic acid t aurine (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 equival ent to 500 mg/kg cholestyramine. Two days oral administration of 10 mg /kg 2164U90 to rats decreased the bile concentrations of total bile ac ids 42%, orally administered [H-3]taurocholic acid ([H-3]TC) 82%, and cholesterol 35%. Cholestyramine (500 mg/kg) had effects similar to 216 4U90 on total bile acid and orally administered [H-3]TC concentrations but had no effect on biliary cholesterol. The hypocholesterolemic act ivity of 2164U90 was determined in cholesterol-cholic acid-fed rats an d cholesterol-cholic acid-coconut oil-fed mice. 2164U90 inhibited the dietary-induced increase in dextran sulfate-precipitable lipoprotein c holesterol (VLDL + LDL) at doses comparable to doses needed to increas e the fecal excretion of bile acids. These data indicate that 2164U90 decreases bile acid absorption by inhibiting the ileal bile acid activ e transport system, resulting in hypocholesterolemic activity.