Premium
Omeprazole preferentially inhibits the metabolism of (+)‐(S)‐citalopram in healthy volunteers
Author(s) -
Rocha Adriana,
Coelho Eduardo B.,
Sampaio Stefânia A.,
Lanchote Vera L.
Publication year - 2010
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/j.1365-2125.2010.03649.x
Subject(s) - omeprazole , pharmacokinetics , cyp2c19 , chemistry , pharmacology , oral administration , metabolism , medicine , cytochrome p450 , biochemistry
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.