INTERACTION BETWEEN GRAPEFRUIT JUICE AND MIDAZOLAM IN HUMANS

Objective: To investigate the effects of grapefruit juice on the pharm acokinetics and dynamics of midazolam. Methods: Eight healthy male sub jects 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 pharmacodyn amics (reaction time, Digit Symbol Substitution Test [DSST], general i mpression judged by the investigators, and drug effect judged by the s ubjects) of midazolam and the pharmacokinetics of alpha-hydroxymidazol am. Results: In comparison to water, pretreatment with grapefruit juic e did not change the pharmacokinetics or pharmacodynamics of intraveno us midazolam, After oral administration, pretreatment with grapefruit juice led to a 56% increase in peak plasma concentration (C-max), a 79 % increase in time to reach C-max (t(max)), and a 52% increase in the area under the plasma concentration-time curve (AUC) of midazolam, whi ch was associated with an increase in the bioavailability from 24% +/- 3% (water) to 35% +/- 3% (Grapefruit juice; mean +/- SEM, p < 0.01) A fter oral administration of midazolam, pretreatment with grapefruit ju ice was associated with a 105% increase in Im,and with a 30% increase in the AUC of alpha-hydroxymidazolam. For oral midazolam, pretreatment with grapefruit juice led to significant increases in t(max) for all dynamic parameters and in the AUC values for the reaction time and DSS T, whereas the maximal dynamic effects remained unchanged. Conclusions : Pretreatment with grapefruit juice is associated with increased bioa vailability and changes in the pharmacodynamics of midazolam that may be clinically important, particularly in patients with other causes fo r increased midazolam bioavailability such as advanced age, cirrhosis of the liver, and administration of other inhibitors of cytochrome P45 0.