Comparison of synthetic saponin cholesterol absorption inhibitors in rabbits: evidence for a non-stoichiometric, intestinal mechanism of action.

The hypocholesterolemic activities of pamaqueside and tiqueside, two structurally similar saponins, were evaluated in cholesterol-fed rabbits. The pharmacological profiles of the saponins were virtually identical: both dose-dependently decreased the intestinal absorption of labeled cholesterol 25-75%, increased fecal neutral sterol excretion up to 2.5-fold, and decreased hepatic cholesterol content 10-55%. High doses of pamaqueside (>5 mg/kg) or tiqueside (>125 mg/kg) completely prevented hypercholesterolemia. Decreases in plasma and hepatic cholesterol levels were strongly correlated with increased neutral sterol excretion. Ratios of neutral sterol excreted to pamaqueside administered were greater than 1:1 at all doses, in opposition to the formation of a stoichiometric complex previously suggested for tiqueside and other saponins. Ratios in tiqueside-treated rabbits were less than unity, a reflection of its lower potency. Pamaqueside-treated rabbits exhibited a more rapid decline in plasma cholesterol concentrations than control animals fed a cholesterol-free diet, indicating that the compound also inhibited the absorption of biliary cholesterol. Intravenous administration of pamaqueside had no effect on plasma cholesterol levels despite plasma levels twice those observed in rabbits given pamaqueside orally. These data indicate that pamaqueside and tiqueside induce hypocholesterolemia by blocking lumenal cholesterol absorption via a mechanism that apparently differs from the stoichiometric complexation of cholesterol hypothesized for other saponins.

Pharmacological properties of a novel ACAT inhibitor (CP-113,818) in cholesterol-fed rats, hamsters, rabbits, and monkeys.

The novel acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor CP-113,818 has been characterized in vitro against ACAT isolated from liver and intestine from a variety of species including human subjects, and in vivo in cholesterol-fed rats, hamsters, rabbits, and two species of nonhuman primates. CP-113,818 is a potent and specific inhibitor of liver and intestinal ACAT with IC50s ranging from 17 to 75 nM. This ACAT inhibitor also prevented the absorption of exogenous radiolabeled cholesterol in hamsters (ED50 = 6 micrograms/kg), rabbits (ED50 1/2 10 micrograms/kg), and cynomolgus and African green monkeys (40 and 26% inhibition at 10 mg/kg, respectively). CP-113,818 effectively prevented the increase in liver cholesterol levels in cholesterol-fed rats, hamsters, and rabbits. In lipoprotein characterization studies in rabbits, CP-113,818 selectively decreased apoB-containing lipoproteins (beta-VLDL, IDL, and LDL) and shifted the distribution of cholesterol from beta-VLDL, IDL, and LDL (96% before treatment to 81% after treatment) to HDL (4% before treatment to 19% after treatment). Finally, in monkeys, CP-113,818 significantly decreased LDL cholesterol by approximately 30% while either increasing HDL cholesterol (cynomolgus monkeys) or not affecting HDL cholesterol (African green monkeys), thereby improving the total plasma cholesterol/HDL ratios. In summary, CP-113,818 significantly inhibited cholesterol absorption, prevented the increase in liver cholesterol, and improved the lipoprotein profiles by selectively decreasing the cholesterol concentrations of the atherogenic lipoproteins (VLDL, IDL, and LDL) in a variety of cholesterol-fed animals. These data suggest that ACAT inhibition may be a useful therapeutic approach for lowering LDL cholesterol and thereby reducing the risk of developing coronary heart disease.

Pharmacologic consequences of cholesterol absorption inhibition: alteration in cholesterol metabolism and reduction in plasma cholesterol concentration induced by the synthetic saponin beta-tigogenin cellobioside (CP-88818; tiqueside).

Natural and synthetic saponins inhibit cholesterol absorption and reduce plasma cholesterol levels in experimental animals and are therefore of potential pharmacologic utility in the treatment of hypercholesterolemia. To determine the effects of this class of compounds on cholesterol absorption and metabolism, we evaluated the effects of the synthetic saponin, beta-tigogenin cellobioside (tiqueside; CP-88818), on male golden Syrian hamsters. When administered as either a single oral bolus or as a dietary supplement for up to 2 weeks, tiqueside inhibited cholesterol absorption in a dose-dependent manner in both the presence and absence of dietary cholesterol. Administration of tiqueside to chow-fed hamsters as a 0.2% dietary supplement (150 mg/kg per day) for 4 days resulted in a 68% decrease in intestinal cholesterol absorption with no change in either bile absorption or cholesterol 7 alpha-hydroxylase activity, suggesting that tiqueside inhibits cholesterol absorption without interfering with enterohepatic bile acid recirculation. Under these conditions, hepatic cholesterol levels were also reduced in a dose-dependent manner. Hepatic cholesterol reduction was highly correlated with cholesterol absorption inhibition, and induced compensatory increases in both hepatic HMG-CoA reductase activity and hepatic low density lipoprotein (LDL) receptor levels. Compensatory increases in intestinal HMG-CoA reductase activity were also noted after tiqueside administration, and are consistent with a luminal mechanism for tiqueside action. As a consequence of these changes to cholesterol metabolism, tiqueside administration induced plasma cholesterol reductions that were highly correlated with both hepatic cholesterol reduction and cholesterol absorption inhibition. Tiqueside also produced comparable plasma cholesterol lowering in a variety of other species fed either cholesterol-free diets (hamster, rat, mouse, dog) or cholesterol-containing diets (hamster, rat, rabbit, mouse, cynomolgus monkey, rhesus monkey, SEA quail) indicating the ubiquity of tiqueside action. For all species evaluated except the dog, the reduction in plasma cholesterol was due primarily to a reduction in circulating non-HDL cholesterol levels with little or no change in HDL cholesterol levels. Taken together, these results indicate that inhibition of cholesterol absorption by tiqueside produces profound effects on cholesterol metabolism without affecting bile acid metabolism, and that these changes lead to reductions primarily in plasma non-HDL cholesterol concentrations. The synthetic saponin, tiqueside, may thus represent a prototypical form of therapy for the treatment of hypercholesterolemia.