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The purpose of this research project was to investigate potential matrix effects of anticoagulant and lipemia on the response of olanzapine, desmethyl olanzapine, olanzapine-D-3 and desmethyl olanzapine-D-8 in an LC/MS/MS assay. Blank human serum and sodium heparin, sodium citrate, and K(3)EDTA plasma with various degrees of lipemia were fortified with olanzapine, desmethyl olanzapine, olanzapine-D-3 and desmethyl olanzapine-D-8. Six replicates of each sample were extracted using Waters Oasis(R) MCX cartridges and analyzed using electrospray LC/MS/MS. The analytes were separated on a Phenomenex LUNA phenyl hexyl, 2 mm x 50 mm, 5 mum, analytical column and a gradient rising from 2 to 85% mobile phase B. Mobile phase A consisted of acetonitrile-ammonium acetate (20 mM) (52:48 v/v) and mobile phase B was formic acid-acetonitrile (0.1:100 v/v). Ion suppression was investigated through post column infusion experiments. The degree of lipemia of each sample, indicated by turbidity, was ranked into categories from least to greatest and used for statistical analyses. The results from analysis of variance testing indicated that lipemia, anticoagulant and their interaction significantly influenced mass spectral matrix effects and extraction matrix effects. Differential behavior between the analytes and labeled internal standards contributed to variability. The most significant source of variability however, was ion suppression due to co-eluting matrix components. (C) 2004 Elsevier B.V. All rights reserved.