Chirality in the new generation of antidepressants: stereoselective analysis of the enantiomers of mirtazapine, N-demethylmirtazapine, and 8-hydroxymirtazapine by LC-MS.
Mirtazapine is an antidepressant that acts specifically on noradrenergic and sertonergic receptors. A LC-MS method was developed that allows the simultaneous analysis of the R-(-)- and S-(+)-enantiomers of mirtazapine (MIR), demethylmirtazapine (DMIR), and 8-hydroxymirtazapine (8-OH-MIR) in plasma of MIR-treated patients. The method involves a 3-step liquid-liquid extraction, an HPLC separation on a Chirobiotic V column, and MS detection in electrospray mode. The limit of quantification (LOQ) for all enantiomers was 0.5 ng/mL, and the intra- and interday CVs were within 3.3% to 11.7% (concentration ranges 5-50 ng/mL). A method is also presented for the quantitative analysis of glucuroconjugated MIR and 8-OH-MIR. S-(+)-8-OH-MIR is present in plasma mainly as its glucuronide. Preliminary data suggest that in all patients, except in those comedicated with CYP2D6 inhibitors such as fluoxetine and thioridazine, R-(-)-MIR concentrations were higher than those of S-(+)MIR. Moreover, fluvoxamine seems also to inhibit the metabolism of MIR. Therefore, this method seems to be suitable for the stereoselective assay of MIR and its metabolites in plasma of patients comedicated with MIR and other drugs for routine and research purposes.
Paus
Erik
E
Unité de Biochimie et Psychopharmacologie Clinique, University Department of Adult Psychiatry, Site de Cery, CH-1008 Prilly-Lausanne, Switzerland.
Jonzier-Perey
Michèle
M
Cochard
Nathalie
N
Eap
Chin B
CB
Baumann
Pierre
P
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000929:Antidepressive Agents, Tricyclic / Q000097:blood* / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid; D002853:Chromatography, Liquid; D005260:Female; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D008803:Mianserin / Q000031:analogs & derivatives* / Q000032:analysis / Q000097:blood* / Q000737:chemistry; D008875:Middle Aged; D000078785:Mirtazapine; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D013237:Stereoisomerism
D000929:Antidepressive Agents, Tricyclic; D008803:Mianserin; D000078785:Mirtazapine; C415843:8-hydroxymirtazapine; C119256:demethylmirtazapine