I. Excretory products of the sterol biosynthetic pathway in the MER-29-treated rat II. Excretion of MER-29

MER-29 was previously shown to inhibit cholesterol biosynthesis at a stage in the biosynthetic pathway following the formation of the sterol nucleus. Theoretically, this action could cause the accumulation of sterol precursors of cholesterol, while reducing the level of cholesterol itself in animal tissues.

Under conditions of-almost complete inhibition of cholesterol biosynthesis in the rat, both cholesterol and total unsaponifiable matter are reduced in plasma; in liver, lung and spleen, cholesterol is reduced, and unsaponifiable matter is either unchanged or reduced slightly. Overall, therefore, cholesterol precursors do not appear to accumulate in sufficient quantity to make up the cholesterol deficit entirely.

The fate of the precursors was determined by following the fecal excretion of radioactivity derived from labelled mevalonic acid in MER-29-treated rats. These rats, like controls, excreted the label in the fecal bile acids and unsaponifiable matter, indicating the fate of the cholesterol precursors. There was an increased turnover of the sterol pathway in the MER-29-treated animals, reflecting reduced pool of labelled intermediates. A slightly greater fraction of the excreted radioactivity appeared in the bile acid fraction in the MER-29 rats, indicating that the sterols occurring immediately before the site of inhibition may be more readily converted to bile acids than is cholesterol.

The excretion of MER-29 was followed after oral administration of the drug labelled in a central position with carbon-14. The principal route of excretion is in the feces, which accounted for 30 per cent of the administered dose in 48 hours; 7 per cent occurred in urine. The material excreted in urine was not unchanged drug. In bile fistula rats, 23 per cent of an oral dose of MER-29 was excreted in the bile in 24 hours.