SENSITIVE, HIGH-THROUGHPUT GAS-CHROMATOGRAPHIC MASS-SPECTROMETRIC ASSAY FOR FLUOXETINE AND NORFLUOXETINE IN HUMAN PLASMA AND ITS APPLICATION TO PHARMACOKINETIC STUDIES

A sensitive, robust gas chromatographic-mass spectrometric assay suita ble for use in pharmacokinetic or bioequivalence studies is presented for the selective serotonin reuptake inhibitor, fluoxetine, and its ma jor metabolite, norfluoxetine (N-desmethylfluoxetine). This method emp loys solid-phase extraction followed by acetylation with trifluoroacet ic anhydride and analysis of the derivatives using selected ion monito ring. The lower limit of quantification was 1.0 ng/ml, and the assay w as linear for both analytes from 1 to 100 ng/ml. Mean recoveries follo wing solid-phase extraction at concentrations of 5.0, 20 and 100 ng/ml were 91% (fluoxetine) and 87% (norfluoxetine). Assay precision (as me an RSD) and accuracy (as mean relative error) for both analytes were t ested at the same three nominal concentrations and were found to be wi thin 10% in all cases. Analysis of fluoxetine concentrations in plasma samples from 18 volunteers following administration of a single 40 mg dose of fluoxetine provided the following pharmacokinetic data (mean/-SD): C-max, 32.73+/-9.21 ng/ml; AUC(0-infinity), 1627+/-1372 ng/ml h ; T-max, 3.08 h (median); k(e), 0.022+/-0.007 h(-1); elimination half- life, 37.69+/-21.70 h. (C) 1998 Elsevier Science B.V. All rights reser ved.