EFFECTS OF TRIPARANOL (MER-29) ON CHOLESTEROL BIOSYNTHESIS AND ON BLOOD STEROL LEVELS IN MAN*

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Abstract
Triparanol (100 mg-250 mg daily) was given to 9 patients. In all subjects desmosterol appeared in serum and accounted for 19% to 43% of total sterols (average 27%). Its presence was demonstrated by chromatographic isolation as the p-phenylazobenzoyl ester, by gas-liquid chromatography and by a colorimetric analysis. The proportion of desmosterol in serum sterols was fairly constant in each patient. Desmosterol disappeared within 2 weeks after discontinuation of treatment. Triparanol caused an average drop of 34% in serum cholesterol, but only of 15% in total serum sterols. The free to total ratios for desmosterol and cholesterol in serum were approximately equal. A method for determination of desmosterol and cholesterol in a single sample based on the Liebermann-Burchard reaction is described. It is shown that in the presence of desmosterol, standard methods for determination of cholesterol, based on that reaction, yield falsely low results for total sterols. Four hours after intravenous injection of 2-C14- mevalonic acid in patients receiving triparanol, the specific radioactivity of serum desmosterol was 1 or 2 orders of magnitude higher than that of cholesterol; the two did not become equal until 2 weeks later. The specific radioactivity of esterified desmosterol equaled that of free desmosterol 24 to 48 hours after administration of label. The peak specific radioactivity and the peak total radioactivity of the unfractionated free serum sterols during treatment with triparanol were significantly lower than during control period (by 16% and 24%, respectively). It is concluded that the mechanism of action of triparanol in man is to inhibit the conversion of desmosterol to cholesterol and that the depression of serum cholesterol and total serum sterol levels is attributable to this inhibition.