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Induction of CYP2C19 and CYP3A Activity Following Repeated Administration of Efavirenz in Healthy Volunteers
Author(s) -
Michaud V,
Ogburn E,
Thong N,
Aregbe A O,
Quigg T C,
Flockhart D A,
Desta Z
Publication year - 2012
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/clpt.2011.249
Subject(s) - omeprazole , efavirenz , cyp2c19 , cyp3a , pharmacology , pharmacokinetics , chemistry , cyp3a4 , cyp2b6 , oral administration , drug interaction , metabolism , medicine , cytochrome p450 , biochemistry , immunology , human immunodeficiency virus (hiv) , antiretroviral therapy , viral load
drug–drug interactions involving efavirenz are of major concern in clinical practice. We evaluated the effects of multiple doses of efavirenz on omeprazole 5‐hydroxylation (CYP2C19) and sulfoxidation (CYP3A). Healthy volunteers ( n = 57) were administered a single 20 mg oral dose of racemic omeprazole either with a single 600 mg oral dose of efavirenz or after 17 days of administration of 600 mg/day of efavirenz. The concentrations of racemic omeprazole, 5‐hydroxyomeoprazole (and their enantiomers), and omeprazole sulfone in plasma were measured using a chiral liquid chromatography–tandem mass spectrometry method. Relative to single‐dose treatment, multiple doses of efavirenz significantly decreased ( P < 0.0001) the area under the plasma concentration–time curve from 0 to infinity (AUC 0–∞ ) of racemic‐, R‐ and S‐omeprazole (2.01‐ to 2.15‐fold) and the corresponding AUC 0–∞ metabolic ratio (MR) for 5‐hydroxyomeprazole (1.36‐ to 1.44‐fold) as well as the MR for omeprazole sulfone (∼2.0) ( P < 0.0001). The significant reduction in the AUC of 5‐hydroxyomeprazole after repeated efavirenz dosing suggests induction of sequential metabolism and mixed inductive/inhibitory effects of efavirenz on CYP2C19. In conclusion, efavirenz enhances omeprazole metabolism in a nonstereoselective manner through induction of CYP3A and CYP2C19 activity. Clinical Pharmacology & Therapeutics (2012); 91 3, 475–482. doi: 10.1038/clpt.2011.249