Omeprazole preferentially inhibits the metabolism of (+)-(S)-citalopram in healthy volunteers
Article first published online: 24 FEB 2010
© 2010 The Authors. Journal compilation © 2010 The British Pharmacological Society
British Journal of Clinical Pharmacology
Volume 70, Issue 1, pages 43–51, July 2010
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
- Issue published online: 11 JUN 2010
- Article first published online: 24 FEB 2010
- Received 10 November 2008Accepted12 January 2010
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.
The study assessed the influence of omeprazole on the kinetic disposition of the (+)-(S)-citalopram (CITA) and (−)-(R)-CITA enantiomers in healthy volunteers.
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.
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].
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.