Measurement of Clozapine, Norclozapine, and Amisulpride in Plasma and in Oral Fluid Obtained Using 2 Different Sampling Systems

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There is a poor correlation between total concentrations of proton-accepting compounds (most basic drugs) in unstimulated oral fluid and in plasma. The aim of this study was to compare clozapine, norclozapine, and amisulpride concentrations in plasma and in oral fluid collected using commercially available collection devices [Thermo Fisher Scientific Oral-Eze and Greiner Bio-One (GBO)].


Oral-Eze and GBO samples and plasma were collected in that order from patients prescribed clozapine. Analyte concentrations were measured by liquid chromatography–tandem mass spectrometry.


There were 112 participants [96 men, aged (median, range) 47 (21–65) years and 16 women, aged 44 (21–65) years]: 74 participants provided 2 sets of samples and 7 provided 3 sets (overall 2 GBO samples not collected). Twenty-three patients were co-prescribed amisulpride, of whom 17 provided 2 sets of samples and 1 provided 3 sets. The median (range) oral fluid within the GBO samples was 52 (13%–86%). Nonadherence to clozapine was identified in all 3 samples in one instance. After correction for oral fluid content, analyte concentrations in the GBO and Oral-Eze samples were poorly correlated with plasma clozapine and norclozapine (R2 = 0.57–0.63) and plasma amisulpride (R2 = 0.65–0.72). Analyte concentrations in the 2 sets of oral fluid samples were likewise poorly correlated (R2 = 0.68–0.84). Mean (SD) plasma clozapine and norclozapine were 0.60 (0.46) and 0.25 (0.21) mg/L, respectively. Mean clozapine and norclozapine concentrations in the 2 sets of oral fluid samples were similar to those in plasma (0.9–1.8 times higher), that is, approximately 2- to 3-fold higher than those in unstimulated oral fluid. The mean (±SD) amisulpride concentrations (microgram per liter) in plasma (446 ± 297) and in the Oral-Eze samples (501 ± 461) were comparable and much higher than those in the GBO samples (233 ± 318).


Oral fluid collected using either the GBO system or the Oral-Eze system cannot be used for quantitative clozapine and/or amisulpride therapeutic drug monitoring.

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