PHARMACOKINETIC PROPERTIES OF YM17E, AN INHIBITOR OF ACYL-COENZYME-A - CHOLESTEROL ACYL TRANSFERASE, AND SERUM-CHOLESTEROL LEVELS IN HEALTHY-VOLUNTEERS

We conducted a single and repeat oral dose study of YM17E, a novel inh ibitor of acyl coenzyme A (CoA): cholesterol acyltransferase, in healt hy male volunteers to evaluate the pharmacokinetic profile, tolerabili ty and effect of the drug on serum cholesterol. In the single administ ration study, YM17E was administered after a meal to two groups of sub jects (each containing six subjects taking the drug and three taking p lacebo) receiving 3, 60 and 300 mg or 15, 60 and 450 mg YM17E, respect ively. Plasma concentrations of unchanged drug following single oral a dministration at 3-300 mg after a meal increased with increasing dose. In contrast, plasma concentrations after administration of 450 mg wer e almost the same as after 300 mg. Unchanged YM17E was not detected in urine after single administration, suggesting that it was excreted vi a the bile or urine after metabolism. Five active metabolites (Mi, M2- a, M2-b, M3 and M4) were observed in plasma at concentrations comparab le to those of unchanged YM17E. Their plasma concentrations increased in a slightly greater than dose-dependent manner from 3 to 300 mg.The effect of food was studied in an open crossover design with a 1-week w ashout period. Twelve subjects received 150 mg YM17E in both the faste d and postprandial states. The AUC and C-max after fasting were closel y similar to those after a meal, showing that bioavailability was not affected by food intake. In the repeated oral dose study, the subjects received test drug at 150 mg or 300 mg (n = 6 each) or placebo (n = 3 ) twice a day (after breakfast and after dinner) for 7 days. On days 1 and 7, the subjects received YM17E once a day (after breakfast) for e valuation of pharmacokinetic properties. After repeated oral administr ation of 150 mg b.d., plasma concentrations reached steady state by da y 5 (mean C-min 48.6 ng . ml(-1)). After repeated administration of 30 0 mg b.d., plasma concentrations prior to each daily morning dose incr eased up to the 5th day (mean C-min 166.6 ng . ml(-1)) and then tended to decrease until the 7th day. No significant signs, symptoms or chan ges in serum cholesterol levels were observed during the single and re peated oral dose studies at 150 mg b.d. Although statistical analysis was not conducted because of the small number of subjects, all subject s receiving repeated oral administration of 300 mg twice daily showed a 25% decrease in serum cholesterol level on day 7, but also the simul taneous occurrence of diarrhoea.