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- Title
Effect of extended exposure to grapefruit juice on cytochrome P450 3A activity in humans: Comparison with ritonavir<sup>*</sup>.
- Authors
Culm-Merdek, Kerry E.; von Moltke, Lisa L.; Lu Gan; Horan, Kelly A.; Reynolds, Robyn; Harmatz, Jerold S.; Court, Michael H.; Greenblatt, David J.
- Abstract
Background and Objectives: 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.Methods: 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.Results: 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 β amplitude. Kinetic and dynamic effects reverted to baseline (trial 1) values at 3 days after grapefruit juice discontinuation (trial 4). Ritonavir caused a more than 20-fold increase in the triazolam area under the plasma concentration curve during trial 2 (553 ± 422 ng/mL·h) and trial 3 (287 ± 299 ng/mL·h) compared to the trial 1 control (13.3 ± 16.3 ng/mL·h) (P < .05 for both comparisons); Digit Symbol Substitution Test and electroencephalographic pharmacodynamics increased in parallel. During trial 4, triazolam kinetics reverted close to trial 1 values, with no evidence of induction. Triazolam kinetics were not altered by water cotreatment.Conclusion: Acute and extended exposure to grapefruit juice produces quantitatively similar inhibition of enteric, but not hepatic, CYP3A. Recovery is complete within 3 days after grapefruit juice discontinuation. Ritonavir greatly inhibits both enteric and hepatic CYP3A. With extended exposure to ritonavir, inhibition is the predominant effect, and recovery to baseline is nearly complete 3 days after ritonavir discontinuation.Clinical Pharmacology & Therapeutics (2006) 79, 243–254; doi: 10.1016/j.clpt.2005.11.009
- Subjects
GRAPEFRUIT juice; CYTOCHROME P-450; PHARMACOKINETICS; DRUG interactions; PHARMACODYNAMICS; PROTEASE inhibitors
- Publication
Clinical Pharmacology & Therapeutics, 2006, Vol 79, Issue 3, p243
- ISSN
0009-9236
- Publication type
Article
- DOI
10.1016/j.clpt.2005.11.009