Effect of extended exposure to grapefruit juice on cytochrome P450 3A activity in humans: comparison with ritonavir

Clinical Pharmacology and Therapeutics
Kerry E Culm-MerdekDavid J Greenblatt

Abstract

Acute ingestion of usual quantities of grapefruit juice produces inhibition of enteric cytochrome P450 (CYP) 3A enzymes, causing pharmacokinetic interactions with a number of drugs. However, the effect of extended exposure to grapefruit juice on CYP3A activity is not established. Triazolam, a CYP3A index compound, was administered to 3 cohorts of volunteers (n = 6-7 per group) on 4 occasions (trials 1-4), as follows: 1 day prior to cotreatment initiation, at the beginning and end of cotreatment, and 3 days after cotreatment discontinuation. The 3 cotreatments (daily administration for 10 consecutive days) were: 300 mL grapefruit juice, 400 mg ritonavir, or 300 mL water. Grapefruit juice cotreatment (trial 2) increased the triazolam area under the plasma concentration curve by 50% compared to the trial 1 control (15.1 +/- 7.6 ng/mL.h versus 10.0 +/- 3.5 ng/mL.h, P < .05), but the half-life was not changed. Effects of acute and extended exposure to grapefruit juice (trials 2 and 3) were similar, and produced augmentation in benzodiazepine agonist effects measured by the Digit Symbol Substitution Test and electroencephalographic beta amplitude. Kinetic and dynamic effects reverted to baseline (trial 1) values at 3 days after grape...Continue Reading

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