Inhibitors of sterol synthesis. Metabolism of [2,4-3H]5 alpha-cholest-8(14)-en-3 beta-ol-15-one after oral administration to a nonhuman primate.

5 alpha-Cholest-8(14)-en-3 beta-ol-15-one is a potent inhibitor of cholesterol biosynthesis which has significant hypocholesterolemic activity upon oral administration to rodents and nonhuman primates. In the present study the metabolism of the 15-ketosterol has been investigated after the oral administration of a mixture of [2,4-3H]5 alpha-cholest-8(14)-en-3 beta-ol-15-one and [4-14C]cholesterol to 8 baboons. Blood samples were obtained at 4, 8, 12, 16, and 24 h after administration of the labeled sterols. Clear differences in the time courses of the levels of 3H and 14C in plasma were observed. 3H in plasma showed maximum values at 4 to 8 h, whereas maximum values for the levels of 14C were observed much later. 3H in plasma was shown to be primarily in the form of its metabolites, i.e. esters of the 15-ketosterol, cholesterol, and cholesteryl esters. The levels of the 15-ketosterol and of each of these metabolites showed different changes with time. The labeled cholesterol (and the cholesterol moiety of the cholesteryl esters), formed from the [2,4-3H]-15-ketosterol, was characterized by chromatography and by purification by way of its dibromide derivative. At 24 h after the administration of the labeled sterols, the distribution of 3H in plasma lipoprotein fractions paralleled that of 14C, with most of the 3H and 14C in high density lipoprotiens (HDL) and low density lipoproteins (LDL). Almost all of the 3H in HDL and in LDL was found as cholesterol, cholesteryl esters and esters of the 15-ketosterol. The distribution of 3H in HDL and in LDL of the free 15-ketosterol, esters of the 15-ketosterol, cholesterol, and cholesteryl esters was similar to that of plasma, thereby indicating no unusual concentration of any of the 3H labeled components in HDL or LDL.