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

• Published in: Clinical pharmacology and therapeutics Vol. 79; no. 3; pp. 243 - 254
• Main Authors: Culm‐Merdek, Kerry E., Moltke, Lisa L., Gan, Lu, Horan, Kelly A., Reynolds, Robyn, Harmatz, Jerold S., Court, Michael H., Greenblatt, David J.
• Format: Journal Article
• Language: English
• Published: New York, NY Nature Publishing 01-03-2006
• Subjects: Adolescent; Adult; Area Under Curve; Benzodiazepines - pharmacokinetics; Beverages; Biological and medical sciences; Chromatography, Liquid; Citrus paradisi; Cytochrome P-450 CYP3A - metabolism; Female; Food-Drug Interactions; HIV Protease Inhibitors - pharmacokinetics; Humans; Liver - drug effects; Liver - enzymology; Male; Mass Spectrometry; Medical sciences; Middle Aged; Pharmacology. Drug treatments; Ritonavir - pharmacokinetics; Human; Antiretroviral agent; Enzyme; Isozyme; Ritonavir; Cytochrome P450; Enzyme inhibitor; Exposure; Fruit juice; Biological activity; Peptidases; Hydrolases; Antiviral; Grapefruit; Protease inhibitor; Comparative study
• ISSN: 0009-9236; 1532-6535
• DOI: 10.1016/j.clpt.2005.11.009

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