HYPOLIPEMIC PROPERTIES OF A POTENT AND BIOAVAILABLE ALKLYSULFINYL-DIPHENYLIMIDAZOLE ACAT INHIBITOR (RP-73163) IN ANIMALS FED DIETS LOW IN CHOLESTEROL

RP 73163 zolyl)pent-1-yl)-sulphinyl]-5,6-diphenylimidazole) has been s hown to be a potent and specific inhibitor of acyl-CoA:cholesterol acy ltransferase (EC 2.3.1.26; ACAT) in vitro using the tissues of experim ental animals as sources of the enzyme. The concentrations of RP 73163 required to produce 50% inhibition of ACAT activity (IC50 values) in microsomal preparations ranged from 86 nM for rat liver to 370 nM for rabbit intestine. In whole cell assays using human hepatic (HepG2), in testinal (Caco2), and monocytic (THP-1) cell lines, RP 73163 inhibited ACAT activity with IC50 values of 266, 158, and 314 nM, respectively. The addition of RP 73163 (0.03-1.0 mu M) to the medium of cultured He pG2 cells produced a concentration-dependent decrease in apolipoprotei n B (apoB) secretion. The compound has high systemic bioavailability. Using a bioassay, a concentration of active inhibitor equivalent to 29 mu M of parent compound was present in plasma 1 hr after oral adminis tration of RP 73163 (50 mg . kg(-1)). In rats that had been fed a basa l diet ad libitum or starved for 18 hr prior to blood sampling, the ad ministration of RP 73163 (50 mg . kg(-1) b.i.d. for 7 days) reduced pl asma triglyceride levels by 50% without affecting the concentration of cholesterol. This hypotriglyceridaemic effect was associated with red uctions in plasma very-low-density-lipoprotein (VLDL) and low-density- lipoprotein (LDL) levels. RP 73163 decreased the rate of VLDL secretio n hy 24% in Triton WR-1339-treated rats that had been fasted overnight but did not affect the secretion rate in animals fed ad libitum, indi cating that ACAT was only important in regulating VLDL secretion under certain nutritional conditions. RP 73163 reduced the accumulation of intraperitoneally administered [H-3]leucine into the plasma VLDL-apoB pool in both fed anal fasted states. The results suggest that, in fed animals at least, an increase in the clearance of VLDL from the bloods tream may contribute to the hypolipidaemic activity of the compound. I n rabbits with casein-induced endogenous hypercholesterolaemia, RP 731 63 specifically reduced the levels of cholesterol carried by LDL. In c onclusion, the hypolipidaemic actions of RP 73163, a potent and system ically bioavailable ACAT inhibitor, are consistent with a reduction in the secretion of apoB containing lipoproteins by hepatic tissue and p ossibly with an increase in the clearance of these particles.