Fluphenazine sulfoxide

A comparison of biotransformation patterns in patients receiving oral fluphenazine versus intramuscularly injected fluphenazine decanoate revealed a significant first pass effect (422,427). Thus, plasma ratios of fluphenazine sulfoxide and 7-hydroxy-fluphenazine to fluphenazine were much higher after oral administration compared with intramuscular administration of fluphenazine decanoate. The plasma ratios of fluphenazine-N-oxide to fluphenazine did not differ between the two dosage forms. In a study measuring fluphenazine serum levels during reduced dose fluphenazine decanoate maintenance therapy at two dose levels, it was determined that serum levels could be monitored at maintenance doses (429,430). 

KK Midha, et al. Radioimmunoassay for fluphenazine sulfoxide in human plasma. J Pharmacol Methods 19 63, 1988. 

II) and fluphenazine sulfoxide (III) were identified in the excreta and all the tissues studied. However in the brain only fluphenazine was found. The hydrolysis in the brain of fluphenazine enanthate to fluphenazine was demonstrated. 

Use of serial GCEs [electrode 1 (A) —0.8 V, (B) 0 V electrode 2 (A) and (B) +0.85 V V5 Ag/AgCl] to facilitate the ED of fluphenazine sulfoxide. Column 300x3.9 (i.d.) mm x Bondpak ODS-silica 10 m. Eluent methanol-formic acid (0.15 mol containing dibutylamine (10 mmol L j, pH3.2 (50 + 50) Flow-rate 2.0 mL min Injection lyophilised 3-methyl-1-butanol (isopenta-nol) extract of plasma containing added fluphenazine, fluphenazine sulfoxide and other fluphenazine metabolites (amounts and injection volume not given) Peaks 1 = fluphenazine sulfoxide, 2 = 7-hydroxyfluphenazine, 3 = 8-hydroxyfluphenazine, 4 = fluphenazine, 5 = fluphenazine N-oxide. 

In recent years, dual glassy carbon electrodes have been used either in parallel (to increase the surface area of the electrode and hence the response) or in series. In this instance several modes of operation become possible as discussed for coulo-metric operation below (Section 5). An example of the application of serial glassy carbon electrodes is given by the use of a negative potential (—0.8 V V5 Ag/AgCl) at the first electrode to reduce fluphenazine sulfoxide to fluphenazine, which can then be detected at the second electrode (Figure 3.7) held at +0.8 V vs Ag/AgCl. 

Gas-Liquid Chromatographic Analysis of Fluphenazine and Fluphenazine Sulfoxide in the Urine of Chronic Schizophrenic Patients J. Chromatogr. 75(2) 294-297 (1973) ... 

The API fluphenazine enanthate undergoes oxidation of a secondary aryl thioether to the resulting sulfoxide (Fig. 74) (112). 

Figure 74 Oxidation of the thioether of fluphenazine enanthate to the sulfoxide.

Of the numerous phenothiazines possessing piperazinylpropyl side-chains, fluphena-zine has been the most studied in terms of its pharmacokinetic properties. The apparent reason for the interest in fluphenazine is that it is available in both oral and depot injectable dosage forms. Oral fluphenazine experiences extensive first pass metabolism (419-422) to form numerous metabolites, all of which are less active than the parent drug (410, 420-426). A distribution study of orally administered fluphenazine using radioimmunoassay established that brain concentrations of fluphenazine exceeded plasma concentrations by 10 to 27 times (420). The inactive sulfoxide was the major metabolite found in brain, while brain levels of 7-hydroxy-fluphenazine and fluphenazine-N-oxide were very low (420). It was concluded that metabolites do not contribute to the pharmacology of fluphenazine and that only the plasma level of the parent drug needs be monitored for correlation to therapeutic response. 

Simultaneous alprazolam, chlorpromazine, chlorprothixene, clomipramine, desmethyli-mipramine, diazepam, flunitrazepam, fluphenazine, haloperidol, imipramine, maproti-line, perphenazine, promethazine, protriptyline, thioridazine, thioridazine sulfone, thioridazine sulfoxide, zimeldine, zuclopenthixol... 

Fluphenazine Fluphenazine Fluphena-enanthate sulfoxide zine... 

Fluphenazine Fluphenazine Fluphenazine enanthate dihydrochloride sulfoxide... 

The radical can also be formed by an oxidizing agent, such as ceric ammonium sulfate.In phenothiazines generally, the semiquinone radical undergoes disproportionation. The products of oxidation are the sulfoxide or the 3(or 7)-hydroxy-derivatives. However, formation of the latter is severely inhibited in 10-substituted phenothiazines. The second-order decay rate constant of the semiquinone radical of fluphenazine was found to be 1100 (1/mole/min), as measured by electron spin resonance.The sulfoxide content of several commercial batches of fluphenazine was determined to be around 0.1% by... 

Acetylfluphenazine (VI, Figure 5) was hydrolyzed enzymatically to fluphenazine (I) iui, vitro by homogenates of small intestinal mucosa, liver, and brain from either the rat or the monkey.29 (See also section 7). When fluphenazine was incubated with a "microsomal and soluble" fraction of rat livers, hydroxylation on the phenothiazine ring was observed. 30 sulfoxide was not de-... 

Sackett and McCreery " " have measured the observed second-order rate constants for reaction of a number of phenothiazine cation radicals. Some typical values in phosphate buffer at pH 3.7 are shown in Table 4. The cation radicals shown in this table all give rise to equimolar yields of sulfoxide and parent phenothiazine. However, the kinetics of decay of the cation radicals of chlorpromazine, promazine, triflupromazine, nori chlorpromazine, and nor2 chlorpromazine are qualitatively the same whereas in the case of the cation radicals of methoxypromazine and acepromazine the decays are qualitively different. The cation radicals generated from promethazine (6), fluphenazine (7), perphenazine (8), and chlorphenethazine (9) did not give rise to equal yields of the sulfoxide and parent phenothiazine, but give lower yields of the... 

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