89351
document
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 inhibitor of acyl coenzyme A ( CoA ) : cholesterol acyltransferase , in healthy male volunteers to evaluate the pharmacokinetic profile , tolerability and effect of the drug on serum cholesterol . In the single administration study , YM17E was administered after a meal to two groups of subjects ( each containing six subjects taking the drug and three taking placebo ) receiving 3 , 60 and 300 mg or 15 , 60 and 450 mg YM17E , respectively . Plasma concentrations of unchanged drug following single oral administration at 3-300 mg after a meal increased with increasing dose . In contrast , plasma concentrations after administration of 450 mg were almost the same as after 300 mg . Unchanged YM17E was not detected in urine after single administration , suggesting that it was excreted via the bile or urine after metabolism . Five active metabolites ( M1 , M2-a , M2-b , M3 and M4 ) were observed in plasma at concentrations comparable 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 washout period . Twelve subjects received 150 mg YM17E in both the fasted and post-prandial states . The AUC and Cmax after fasting were closely 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 evaluation of pharmacokinetic properties . After repeated oral administration of 150 mg b.d. , plasma concentrations reached steady state by day 5 ( mean Cmin 48.6 ng.ml-1 ) . After repeated administration of 300 mg b.d. , plasma concentrations prior to each daily morning dose increased up to the 5th day ( mean Cmin 166.6 ng.ml-1 ) and then tended to decrease until the 7th day . No significant signs , symptoms or changes in serum cholesterol levels were observed during the single and repeated oral dose studies at 150 mg b.d . Although statistical analysis was not conducted because of the small number of subjects , all subjects receiving repeated oral administration of 300 mg twice daily showed a 25 % decrease in serum cholesterol level on day 7 , but also the simultaneous occurrence of diarrhoea .
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Intervention_Pharmacological
YM17E , an inhibitor of acyl coenzyme
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Intervention_Pharmacological
dose study of YM17E
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Intervention_Pharmacological
YM17E was administered after a meal to two groups of subjects
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Intervention_Control
and three taking placebo
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Intervention_Pharmacological
YM17E
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Intervention_Pharmacological
YM17E .
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Intervention_Pharmacological
150 mg YM17E
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Intervention_Pharmacological
test drug at 150 mg or 300 mg
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Intervention_Control
placebo ( n = 3 ) twice a day
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Intervention_Pharmacological
YM17E once a day
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Outcome_Physical
serum cholesterol levels
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Outcome_Other
pharmacokinetic profile
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Outcome_Other
tolerability and effect of the drug on serum cholesterol
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Outcome_Physical
Plasma concentrations
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Outcome_Physical
plasma concentrations
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Outcome_Physical
plasma concentrations
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Outcome_Other
AUC and Cmax
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Outcome_Physical
plasma concentrations
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Outcome_Physical
plasma concentrations
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Outcome_Physical
significant signs , symptoms or changes in serum cholesterol levels
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Outcome_Physical
serum cholesterol
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Outcome_Adverse-effects
diarrhoea
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Participant_Condition
healthy
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Participant_Condition
healthy
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Participant_Sex
male
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Participant_Sample-size
six
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Participant_Sample-size
three