Induction of CYP2C19 and CYP3A activity following repeated administration of efavirenz in healthy volunteers.
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.
Division of Clinical Pharmacology, Department of Medicine, School of Medicine, Indiana University, Indianapolis, Indiana, USA.
V
V
Michaud
E
E
Ogburn
N
N
Thong
A O
AO
Aregbe
T C
TC
Quigg
D A
DA
Flockhart
Z
Z
Desta
D000328:Adult; D000480:Alkynes; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis*; D048588:Benzoxazines / Q000008:administration & dosage*; D003521:Cyclopropanes; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis*; D004347:Drug Interactions; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000097:blood / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D006900:Hydroxylation; D008297:Male; D009853:Omeprazole / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics*; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology
D000480:Alkynes; D048588:Benzoxazines; D003521:Cyclopropanes; D004791:Enzyme Inhibitors; D018894:Reverse Transcriptase Inhibitors; C040450:omeprazole sulfone; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; C104464:CYP3A protein, human; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; C098320:efavirenz; D009853:Omeprazole