Enantioselective analysis of citalopram and demethylcitalopram in human and rat plasma by chiral LC‐MS/MS: Application to pharmacokinetics

Abstract

Citalopram (CITA) is available as a racemic mixture and as a pure enantiomer. Its antidepressive action is related to the (+)-(S)-CITA and to the metabolite (+)-(S)-demethylcitalopram (DCITA). In the present investigation, a method for the analysis of CITA and DCITA enantiomers in human and rat plasma was developed and applied to the study of pharmacokinetics. Plasma samples (1 ml) were extracted at pH 9.0 with toluene:isoamyl alcohol (9:1, v/v). The CITA and DCITA enantiomers were analyzed by LC-MS/MS on a Chiralcel OD-R column. Recovery was higher than 70% for both enantiomers. The quantification limit was 0.1 ng/ml, and linearity was observed up to 500 ng/ml plasma for each CITA and DCITA enantiomer. The method was applied to the study of the kinetic disposition of CITA administered in a single oral dose of 20 mg to a healthy volunteer and in a single dose of 20 mg/kg (by gavage) to Wistar rats (n = 6 for each time). The results showed a higher proportion of the (-)-(R)-CITA in human and rat plasma, with S/R AUC ratios for CITA of 0.28 and 0.44, respectively. S/R AUC ratios of DCITA were 0.48 for rats and 1.04 for the healthy volunteer.

Simultaneous quantification of selective serotonin reuptake inhibitors and metabolites in human plasma by liquid chromatography–electrospray mass spectrometry for therapeutic drug monitoring

“…This approach could decrease the analytical precision, as it is difficult to have a single IS with physico-chemical properties and ionization behavior similar to several analytes. Furthermore, in many publications, a drug was chosen as IS [8,11,[13][14][15][17][18][19][21][22][23]25,30], which could lead to an important interference if the patient had taken this compound. Although stable isotope-labeled IS were used in some methods [10,16,24,[27][28][29]31], no method proposed the quantification of all SSRI with a stable isotope-labeled IS for each matching analyte.…”

“…Methods using gas chromatography (GC) have been proposed [8][9][10], however, separation was mainly performed by HPLC coupled with ultraviolet (UV) [11][12][13][14][15], MS [16][17][18][19][20][21] or MS/MS detection [22][23][24][25][26][27][28][29]. Recently, ultra high performance liquid chromatography (UHPLC)-MS/MS methods have also been proposed [30,31].…”

“…Sample preparation was performed mainly by liquid-liquid extraction [8,9,[11][12][13]16,17,22,23], solid-phase extraction (SPE) [10,14,18,19,24,30], protein precipitation [25,26,31] or on-line SPE using a column-switching system [15,20,21,[27][28][29]. The main drawback of almost all of these methods is that multiple analytes were quantified using the same IS [8][9][10][11][12][13][14][15][16][18][19][20][22][23][24][25][26][27][28][29]. This approach could decrease the analytical precision, as it is difficult to have a single IS with physico-chemical properties and ionization behavior similar to several analytes.…”

Bioequivalence Study of Two Formulations of Escitalopram Oxalate 20 mg Tablets in Healthy Volunteers

“…Escitalopram concentrations in plasma were measured using a bioanalytical method for ultra-high performance liquid chromatography coupled to a single quadrupole mass spectrometer (UHPLC-MS) and in ESI+ mode, previously validated by CECIF following the parameters established in the international guidelines of analytical methods of validation [16][17][18][19][20][21], to demonstrate an adequate sensibility, specificity, linearity, accuracy and precision.…”

Development and Validation of a Chiral HPLC Method for Quantitative Analysis of Enantiomeric Escitalopram

“…17 However, in order to quantitative analyses of the enantiomeric composition of citalopram, various analytical methods have been developed in recent years. [18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34] Most of them are involved in the employment of HPLC or supercritical fluid chromatography (SFC), equipped with chiral stationary phases. This study, presents a new, rapid, accurate, precise and the suitable analytical method for seperation of citalopram and the determination of enantiomeric purity of escitalopram with the chiral column composed of silica-based phenylcarbamated β-cyclodextrin (chiral CD-PH).…”