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Effect of grapefruit juice dose on grapefruit juice-triazolam interaction: repeated consumption prolongs triazolam
J J Lilja1, K T Kivistö, J T Backman
1Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Finland.
Objective:
Grapefruit juice inhibits CYP3A4-mediated metabolism of several drugs during first pass. In this study, the effect of grapefruit juice dose on the extent of grapefruit juice-triazolam interaction was investigated.
Methods:
In a randomised, four-phase, crossover study, 12 healthy volunteers received 0.25 mg triazolam with water, with 200 ml normal-strength or double-strength grapefruit juice or, on the third day of multiple-dose [three times daily (t.i.d.)] administration of double-strength grapefruit juice. Timed blood samples were collected up to 23 h after dosing, and the effects of triazolam were measured with four psychomotor tests up to 10 h after dosing.
Results:
The area under the plasma triazolam concentration time curve (AUC(0-infinity)) was increased by 53% (P < 0.01), 49% (P < 0.01) and 143% (P < 0.001) by a single dose of normal-strength, a single dose of double-strength and multiple-dose administration of double-strength grapefruit juice, respectively. The peak plasma concentration (Cmax) of triazolam was increased by about 40% by a single dose of normal-strength grapefruit juice (P < 0.01) and multiple-dose grapefruit juice (P < 0.01) and by 25% by a single dose of double-strength grapefruit juice (P < 0.05). The elimination half-life (t(1/2)) of triazolam was prolonged by 54% during the multiple-dose grapefruit juice phase (P < 0.001). A significant increase in the pharmacodynamic effects of triazolam was seen during the multiple-dose grapefruit juice phase in the digit symbol substitution test (DSST, P < 0.05), in subjective overall drug effect (P < 0.05) and in subjective drowsiness (P < 0.05).
Conclusions:
Even one glass of grapefruit juice increases plasma triazolam concentrations, but repeated consumption of grapefruit juice produces a significantly greater increase in triazolam concentrations than one glass of juice. The t(1/2) of triazolam is prolonged by repeated consumption of grapefruit juice, probably due to inhibition of hepatic CYP3A4 activity.
Insights
Grapefruit juice significantly increases triazolam levels in the body. Repeated consumption leads to a more pronounced effect than a single dose, impacting drug metabolism and half-life.
Area of Science:
- Pharmacology
- Drug Metabolism
- Drug Interactions
Background:
- Grapefruit juice is known to inhibit CYP3A4, an enzyme crucial for drug metabolism.
- This inhibition can lead to increased plasma concentrations of various medications.
Purpose of the Study:
- To investigate the dose-dependent effect of grapefruit juice on the interaction with triazolam.
- To determine how different amounts and frequencies of grapefruit juice consumption affect triazolam pharmacokinetics and pharmacodynamics.
Main Methods:
- A randomized, four-phase crossover study involving 12 healthy volunteers.
- Administration of triazolam with water, normal-strength grapefruit juice, double-strength grapefruit juice, and multiple doses of double-strength grapefruit juice.
- Collection of blood samples and assessment of psychomotor performance over time.
Main Results:
- Single doses of grapefruit juice increased triazolam's area under the curve (AUC) and peak concentration (Cmax).
- Multiple doses of double-strength grapefruit juice led to a substantial increase in AUC (143%) and prolonged the elimination half-life (t(1/2)) by 54%.
- Enhanced pharmacodynamic effects, including impaired psychomotor performance and increased drowsiness, were observed with repeated grapefruit juice consumption.
Conclusions:
- Even a single serving of grapefruit juice elevates triazolam plasma concentrations.
- Repeated consumption of grapefruit juice results in a significantly greater increase in triazolam levels compared to a single dose.
- The prolonged half-life of triazolam with repeated grapefruit juice intake is likely due to sustained inhibition of hepatic CYP3A4 activity.