No abstract

The disposition of fluphenazine was investigated in six healthy volunteers following oral administration (5 mg). Using a sensitive and specific GC-MS procedure plasma fluphenazine concentrations were measured up until 32 h after drug administration. Peak plasma concentrations varied widely (range: 0.26-1.06 ng/ml) and were observed at 2.8 +/- 0.5 h following fluphenazine administration. The apparent terminal elimination half-life of fluphenazine was 33.1 +/- 8.1 h. The area under the plasma concentration-time curve differed widely between subjects (range: 7.1-28.6 ng/ml h) suggesting large interindividual differences in the extent of fluphenazine presystemic elimination.

A new gas chromatographic mass spectrometric procedure for the quantitation of fluphenazine in plasma is described. The method relies on the selected ion monitoring of fluphenazine (m/z 406.1563) and perphenazine (m/z 372.1299), the internal standard, after extraction from plasma with 5% isopropanol in n-pentane. Interferences by plasma constituents such as cholesterol are avoided by including an n-hexane wash. This wash step reduced the recovery of fluphenazine and to a greater extent perphenazine, however, it yielded an organic solution relatively free of any peaks with interfering ions. Prior to gas chromatographic mass spectrometric analysis the silyl derivatives of fluphenazine and perphenazine are prepared using N,O-bis(trimethyl-silyl)acetamide. This procedure allows for the quantitation of as low as 78 pg of fluphenazine per ml of plasma using 2.0 ml plasma aliquots with a coefficient of variation of 4.6%. The high specificity and sensitivity demonstrated by this method allows for the first time the monitoring of plasma concentrations of fluphenazine up to 32 h following a single oral dose of 5 mg of the drug.

A procedure which utilizes the specificity of tandem mass spectrometry was developed for the simultaneous quantification of fluphenazine and its stable isotopomer, [ 'H,]fluphenazine, in 1 ml plasma samples, after low oral doses of this antipsychotic agent. The unlabeled and the deuterium labeled-drug were isolated by a selective extraction procedure, derivatized and analyzed under electron impact ionization via the direct insertion probe of a tandem mass spectrometer. Selected reaction monitoring of the lowenergy collision-induced dissociation of analogous major fragment ions to their respective product ions conferred the necessary specificity to allow direct analysis of plasma extracts without the need for a chromatographic separation step. Calibration graph constructed from spiked blank plasma were linear over the range 25-1000 pg ml-' for each isotopomer, with an overall coefficient of variation of 4.82% and 4.72% for fluphenazine and 1'H,]fluphenazine, respectively. The limit of detection was 5 pg ml-I when 1 ml of plasma was used. The described procedure provided sufficient sensitivity and selectivity such that plasma concentrations of fluphenazine and [ 'H, 1 fluphenazine could be followed in schizophrenic patients for 24 h after the simultaneous administration of single oral doses that contain 5 mg each of fluphenazine dihydrochloride and its deuterated isotopomer, [ 'H, 1 fluphenazine dihydrochloride. Endogeaeous plasma constituents and known metabolites of liuphenazine did not interfere in the assay. Virtually superimposable plasma concentration versus time profiles were obtained, demonstrating that the deuterated isotopomer has no significant isotopic effect.