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

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. AIMThe study assessed the influence of omeprazole on the kinetic disposition of the (+)-(S)-citalopram (CITA) and (-)-(R)-CITA enantiomers in healthy volunteers. METHODSIn 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. RESULTSThe kinetic disposition of CITA was enantioselective in the absence of treatment with omeprazole, with the observation of a greater proportion of plasma (-) CONCLUSIONSThe 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.

Escitalopram population pharmacokinetics in people living with human immunodeficiency virus and in the psychiatric population: Drug–drug interactions and probability of target attainment

“…These comedications were all represented by proton‐pump inhibitors. Although several publications already mentioned this interaction, its magnitude varies from weak to moderate . The decrease of 19% in escitalopram clearance when coadministered with at least 1 CYP2C19 inhibitor found in our study is in good agreement with a prediction based on theoretical considerations provided in the DDI‐predictor tool .…”

Clinical relevance of the (S)-citalopram-omeprazole interaction in geriatric patients

“…As a result, revised recommendations stated that the maximum dose should be restricted to 20 mg for those older than 60 years or taking cytochrome P450 (CYP) 2C19 inhibitors [1,2]. However, QT interval prolongation has not been demonstrated for (S)-citalopram in a geriatric population and the clinical relevance of this side effect remains ill defined.On the other hand, omeprazole, a known inhibitor of CYP2C19, interacts with (S)-citalopram increasing the pharmacological effects of (S)-citalopram [3], but the intensity and clinical relevance of this phenomenon are not entirely understood.Thus, we conducted a 6 month, prospective study aimed at evaluating QT interval prolongation as a response marker for (S)-citalopram dosage during co-administration with omeprazole. We analyzed a sample of geriatric inpatients (n = 201) with QT interval measurements obtained 15 days after starting (S)-citalopramomeprazole treatment.…”

“…On the other hand, omeprazole, a known inhibitor of CYP2C19, interacts with (S)-citalopram increasing the pharmacological effects of (S)-citalopram [3], but the intensity and clinical relevance of this phenomenon are not entirely understood.…”

Escitalopram-Induced Progressive Cervical Dystonia

“…Escitalopram is primarily metabolized by CYP2C19 with additional contribution of CYP3A4 particularly at high plasma concentrations. Recent studies have noted that omeprazole inhibits metabolism of the S-enantiomer of citalopram more strongly than the R-enantiomer, 27 with plasma concentrations of S-citalopram being increased by 50%-100% in the presence of omeprazole. 28 Taken together, these findings may explain why Mr. R was preferentially vulnerable to adverse effects from escitalopram compared with his previous trial with racemic citalopram.…”