Br J Clin Pharmacol. 2010 Jul;70(1):43-51. doi: 10.1111/j.1365-2125.2010.03649.x.

Omeprazole preferentially inhibits the metabolism of (+)-(S)-citalopram in healthy volunteers.

Rocha A, Coelho EB, Sampaio SA, Lanchote VL.

Source

Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto-Universidade de São Paulo, Ribeirão Preto, SP, Brazil.

Abstract

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.