Interaction between grapefruit juice and midazolam in humans.
OBJECTIVE
To investigate the effects of grapefruit juice on the pharmacokinetics and dynamics of midazolam.


METHODS
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 [DSST], general impression judged by the investigators, and drug effect judged by the subjects) of midazolam and the pharmacokinetics of alpha-hydroxymidazolam.


RESULTS
In comparison to water, pretreatment with grapefruit juice did not change the pharmacokinetics or pharmacodynamics of intravenous midazolam. After oral administration, pretreatment with grapefruit juice led to a 56% increase in peak plasma concentration (Cmax), a 79% increase in time to reach Cmax (tmax), 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% +/- 3% (water) to 35% +/- 3% (Grapefruit juice; mean +/- SEM, p < 0.01) After oral administration of midazolam, pretreatment with grapefruit juice was associated with a 105% increase in tmax and with a 30% increase in the AUC of alpha-hydroxymidazolam. For oral midazolam, pretreatment with grapefruit juice led to significant increases in tmax for all dynamic parameters and in the AUC values for the reaction time and DSST, whereas the maximal dynamic effects remained unchanged.


CONCLUSIONS
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 midazolam bioavailability such as advanced age, cirrhosis of the liver, and administration of other inhibitors of cytochrome P450.
Kupferschmidt
H H
HH
Division of Clinical Pharmacology and Toxicology, University Hospital, Zürich, Switzerland.
Ha
H R
HR
Ziegler
W H
WH
Meier
P J
PJ
Krähenbühl
S
S
D000284:Administration, Oral; D000328:Adult; D001628:Beverages; D001682:Biological Availability; D002957:Citrus; D018592:Cross-Over Studies; D018565:Food-Drug Interactions; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008874:Midazolam / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology*
D008874:Midazolam