Induction of CYP2C19 and CYP3A activity following repeated administration of efavirenz in healthy volunteers

V. Michaud, E. Ogburn, N. Thong, A. O. Aregbe, T. C. Quigg, D. A. Flockhart, Zeruesenay Desta

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Abstract

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.

Original languageEnglish
Pages (from-to)475-482
Number of pages8
JournalClinical Pharmacology and Therapeutics
Volume91
Issue number3
DOIs
StatePublished - Mar 2012

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efavirenz
Cytochrome P-450 CYP3A
Healthy Volunteers
Omeprazole
Area Under Curve
Cytochrome P-450 CYP2C19
Hydroxylation
Tandem Mass Spectrometry
Drug Interactions
Liquid Chromatography

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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Induction of CYP2C19 and CYP3A activity following repeated administration of efavirenz in healthy volunteers. / Michaud, V.; Ogburn, E.; Thong, N.; Aregbe, A. O.; Quigg, T. C.; Flockhart, D. A.; Desta, Zeruesenay.

In: Clinical Pharmacology and Therapeutics, Vol. 91, No. 3, 03.2012, p. 475-482.

Research output: Contribution to journalArticle

Michaud, V. ; Ogburn, E. ; Thong, N. ; Aregbe, A. O. ; Quigg, T. C. ; Flockhart, D. A. ; Desta, Zeruesenay. / Induction of CYP2C19 and CYP3A activity following repeated administration of efavirenz in healthy volunteers. In: Clinical Pharmacology and Therapeutics. 2012 ; Vol. 91, No. 3. pp. 475-482.
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