O&jeetive: To investigate the effects of grape&tit juice on the pharmacokinetics and dynamics of midaZ4BlanL Met&oh Eight healthy male subjects participated in this open crossover study. Intravenous (5 mg) or oral (15 mg) midazolam was administered after pretreatment with water or grapefruit juice. We measured the pharmacokinetics and pharmacodynamics (reaction time, Digit Symbol Substitution Test [DSSTJ, general impression judged by the investigators, and drug effect judged by the subjects) of midazolam and the pharmacokinetics of o-hydroxymidazolam. Re.&ts: In comparison to water, pretreatment with grapefruit juice did not change the pharmacokiuetics or pharmacodynamics of intravenous midazolam. After oral administration, pretreatment with grapetiuit juice led to a 56% increase in peak plasma concentration (C,,,,), a 79% increase in time to reach C, (fnu), and a 52% increase in the area under the plasma concentration-time curve (AUC) of midazolam, which was associated with an increase in the bioavailability from 24% f 3% (water) to 35% + 3% (Grapefruit juice; mean f SEM, p < 0.01) After oral administration of midazolam, pretreatment with grapefruit juice was associated with a 105% increase in f, and with a 30% increase in the AUC of cx-hydroxymidazolam. For oral midazolam, pretreatment with grapefruit juice led to significant increases in &, for all dynamic parameters and in the AUC values for the reaction time and DSST, whereas the maximal dynamic effects remained unchanged. C&Z&QH.K Pretreatment with grapefruit juice is associated with increased bioavailability and changes in the pharmacodynamics of midazolam that may be clinically important, particularly in patients with other causes for increased midazohun bioavailability such as advanced age, cirrhosis of the liver, and administration of other inhibitors of cytochrome P450. (CLIN I?