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1. Clin Pharmacol Ther. 2012 Feb 8. doi: 10.1038/clpt.2011.249. [Epub ahead of

Induction of CYP2C19 and CYP3A Activity Following Repeated Administration of
Efavirenz in Healthy Volunteers.

Michaud V, Ogburn E, Thong N, Aregbe AO, Quigg TC, Flockhart DA, Desta Z.

Division of Clinical Pharmacology, Department of Medicine, School of Medicine,
Indiana University, Indianapolis, Indiana, USA.

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.

PMID: 22318618 [PubMed - as supplied by publisher]