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Omeprazole preferentially inhibits the metabolism of (+)-(S)-citalopram in healthy volunteers
Article first published online: 24 FEB 2010
DOI: 10.1111/j.1365-2125.2010.03649.x
© 2010 The Authors. Journal compilation © 2010 The British Pharmacological Society
Additional Information
How to Cite
Rocha, A., Coelho, E. B., Sampaio, S. A. and Lanchote, V. L. (2010), Omeprazole preferentially inhibits the metabolism of (+)-(S)-citalopram in healthy volunteers. British Journal of Clinical Pharmacology, 70: 43–51. doi: 10.1111/j.1365-2125.2010.03649.x
Publication History
- Issue published online: 11 JUN 2010
- Article first published online: 24 FEB 2010
- Received 10 November 2008Accepted12 January 2010
- Abstract
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Keywords:
- citalopram;
- enantiomers;
- omeprazole;
- pharmacokinetics
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
• Citalopram (CITA) pharmacokinetics are enantioselective in healthy volunteers and the metabolism of (+)-(S)-CITA to (+)-(S)-DCITA is dependent on CYP2C19. Omeprazole is a potent CYP2C19 inhibitor.
WHAT THIS STUDY ADDS
• This study indicates that omeprazole induces a loss of enantioselectivity in the CITA pharmacokinetics because of the selective inhibition of (+)-(S)-CITA metabolism.
AIM
The study assessed the influence of omeprazole on the kinetic disposition of the (+)-(S)-citalopram (CITA) and (−)-(R)-CITA enantiomers in healthy volunteers.
METHODS
In a cross-over study, healthy volunteers (n= 9) phenotyped as extensive metabolizers of CYP2C19 and CYP2D6 and with an oral midazolam clearance ranging from 10.9 to 149.3 ml min−1 kg−1 received a single dose of racemic CITA (20 mg orally) in combination or not with omeprazole (20 mg day−1 for 18 days). Serial blood samples were collected up to 240 h after CITA administration. CITA and demethylcitalopram (DCITA) enantiomers were analyzed by LC-MS/MS using a Chiralcel® OD-R column.
RESULTS
The kinetic disposition of CITA was enantioselective in the absence of treatment with omeprazole, with the observation of a greater proportion of plasma (−)-(R)-CITA [AUC S : R ratio of 0.53 (95% CI 0.41, 0.66) for CITA and 1.08 (95% CI 0.80, 1.76) for DCITA] than (+)-(S)-CITA. Racemic CITA administration to healthy volunteers in combination with omeprazole showed a loss of enantioselectivity in CITA pharmacokinetics with an increase of approximately 120% in plasma (+)-(S)-CITA concentrations [AUC S : R ratio of 0.95 (95% CI 0.72, 1.10) for CITA and 0.95 (95% CI 0.44, 1.72) for DCITA].
CONCLUSIONS
The administration of multiple doses of omeprazole preferentially inhibited (+)-(S)-CITA metabolism in healthy volunteers. Although omeprazole increased plasma concentrations of (+)-(S)-CITA by approximately 120%, it is difficult to evaluate the clinical outcome because the range of plasma CITA concentrations related to maximum efficacy and minimum risk of adverse effects has not been established.