Disposition and metabolism of a novel diurea inhibitor of acyl CoA: cholesterol acyltransferase (YM17E) in the rat and dog.

1. We have investigated the disposition and metabolism of YM17E after intravenous and oral administration in the rat and dog. 2. Bioavailability of YM17E was 5-9% at oral doses of 3-30 mg/kg in rat, and 9 and 13% at oral doses of 10 and 30 mg/kg in dog. 3. Five N-demethylated metabolites, which have significant pharmacological activity, were found in rat and dog plasma after oral administration. Plasma concentrations of each of these metabolites were comparable with that of unchanged drug. 4. When 14C-YM17E was administered to rat, AUC of unchanged drug was 7% of that of radioactivity. However, AUC of the combined concentration of unchanged drug and five active metabolites was about 50% of that of radioactivity, indicating that the pharmacological activity of the agent was maintained in spite of its biotransformation. 5. After oral administration of 14C-YM17E at a dose of 10 mg/kg to rat, radioactivity was distributed widely to almost all tissues except the brain. The concentration of radioactivity in the liver, one of the target organs, was 65 times higher than that in plasma at 1 h after administration. 6. A significant amount of radioactivity in the liver was located in the microsomal subfraction, which contains much acyl CoA:cholesterol acyl transferase activity. More than 50% of this microsomal radioactivity was derived from unchanged YM17E and five active metabolites. 7. From excretion data in the bile duct-cannulated rat, the absorption ratio of YM17E from the gastrointestinal tract in this species was estimated to be at least 40%, suggesting that the low bioavailability of the drug is due to extensive first-pass metabolism. 8. Some 95% of the administered radioactivity was excreted in the faeces of rat following iv or po doses of 14C-YM17E.