Clinical perspectives of some neuroleptics through development and application of their assays.

Attempts to investigate relationships between plasma levels of neuroleptics and therapeutic outcome in schizophrenic patients have been hampered due to such factors as the chemical nature of these drugs, their metabolism, and the very heterogeneous nature of the disease states. Two clinical studies are described that investigate the relationship between plasma levels of fluphenazine (FLU) and its metabolites and therapeutic outcome in schizophrenic patients. In the first of these studies the levels of FLU and fluphenazine sulfoxide (FLUSO) in schizophrenics receiving either 5 or 25 mg of fluphenazine decanoate (FLUD) intramuscularly every 2 weeks were monitored. Patients given 25 mg of FLUD required 3 months to reach plasma level steady state. The results suggest that such patients, when being switched from the oral to the depot formulation of FLU, should continue to receive oral supplementation during the 1st 3 months after conversion. The relationship between log-transformed plasma levels at 26 and 38 weeks with subsequent psychotic exacerbation was investigated with the use of logistic regression and survival analysis. Both demonstrated significant relationships between FLU plasma levels and a risk of psychotic exacerbation at 26 and 38 weeks. The possibility of any correlations between neurological side effects and plasma concentrations were also investigated, with statistically significant correlations between FLU levels and akinesia found at 2 and 26 weeks. In the second of these studies the levels of FLU, FLUSO, 7-hydroxyfluphenazine (7-OHFLU), and fluphenazine N4'(-)-oxide (FLUNO) in schizophrenics receiving 5, 10, or 20 mg of oral fluphenazine dihydrochloride daily for 4 weeks were monitored. The relationships between log-transformed plasma levels, disabling side effects, and global improvement were examined by logistic regression for the 4-week period. The study showed a significant correlation between increases in both plasma levels and disabling side effects such that at a plasma level of 2.7 ng/ml, approximately 90% of acutely ill patients experienced disabling side effects. Conversely, the study also showed that at a plasma level of 0.67 ng/ml, 48% of patients experienced improvement without the development of disabling side effects. When relationships between metabolite levels, disabling side effects, and global improvement were examined by logistic regression, a stronger correlation between disabling side effects and FLUNO levels than between side effects and FLU levels was found.(ABSTRACT TRUNCATED AT 400 WORDS)

Synthesis of the N-oxides of phenothiazine antipsychotic agents.

Chlorpromazine N-oxide, fluphenazine N4'-oxide, prochlorperazine N4'-oxide, sulforidazine N-oxide, and trifluoperazine N4'-oxide were synthesized by oxidation of the designated nitrogen atom in the N-10 side chain of the respective parent drug with 3-chloroperoxybenzoic acid. In the case of trifluoperazine, a stepwise increase in the amount of oxidant yielded the N1',N4'-dioxide and N1',N4',S-trioxide. The N',S-dioxides of chlorpromazine and sulforidazine were obtained by hydrogen peroxide oxidation of the appropriate parent drug.

The metabolites of chlorpromazine N-oxide in rat bile.

1. The metabolism of chlorpromazine N-oxide was studied in female rats after a 20 mg/kg single i.p. dose. 2. Metabolites identified in urine and faeces were chlorpromazine, 7-hydroxychlorpromazine, chlorpromazine sulphoxide, N-desmethylchlorpromazine and N-desmethylchlorpromazine sulphoxide. As these same five metabolites were previously shown to be present after oral administration this indicates that reduction of chlorpromazine N-oxide occurs not only in the gastrointestinal tract but also at other sites. 3. The metabolism of chlorpromazine N-oxide was studied following its administration by either i.p., i.v. or oral routes to female rats in which the bile duct was cannulated. 4. There were no qualitative differences between the three routes of administration with respect to the metabolites identified. With the exception of the absence of N-desmethylchlorpromazine and N-desmethylchlorpromazine sulphoxide, all metabolites previously identified in urine and faeces were also present in bile. 5. Additionally there were three compounds present in rat bile which were not identified in urine or faeces. These were chlorpromazine N-oxide, chlorpromazine N,S-dioxide and 7-hydroxychlorpromazine O-glucuronide. This is the first unequivocal evidence for the identification of intact 7-hydroxychlorpromazine O-glucuronide in any species. 6. The inability to detect chlorpromazine N-oxide and chlorpromazine N,S-dioxide in the faeces of rats is likely to be due to the reduction of the N-oxide group on the passage of these biliary metabolites down the intestinal tract.

The metabolism of chlorpromazine N-oxide in man and dog.

1. The metabolism of chlorpromazine N-oxide was studied in female dogs and adult male humans after a single oral dose. 2. There was extensive metabolism in both species in that between four and seven metabolites were separately identified in urine and faeces. Apart from chlorpromazine N-oxide, chlorpromazine N,S-dioxide was the only isolated metabolite which retained the N-oxide group. The other identified metabolites were chlorpromazine and its 7-hydroxy, sulphoxide, N-desmethyl, 7-hydroxy-N-desmethyl and N-desmethylsulphoxide derivatives. 3. With dog samples, metabolites were separated by h.p.l.c. and individually collected prior to mass spectrometric analysis. With human samples, metabolites were directly subjected to h.p.l.c.-mass spectrometric determination. With all metabolites their structures were confirmed by direct comparison of their mass spectra and chromatographic behaviours with those of authentic samples. 4. The metabolites identified in urine and faeces were for the most part the same in both species, with the exceptions that chlorpromazine N-oxide was identified in the faeces of dog only and 7-hydroxy-N-desmethylchlorpromazine was identified in the urine of man only. 5. The observation of N-oxide compounds in the excreta of both man and dog contrasted with that for the previously studied rat, where no such compounds were detected.

The metabolism of chlorpromazine N-oxide in the rat.

1. The metabolism of chlorpromazine N-oxide was studied in female rats after a 20 mg/kg single oral dose. 2. Metabolites identified in both urine and faeces were chlorpromazine, 7-hydroxychlorpromazine, chlorpromazine sulphoxide, N-desmethylchlorpromazine and N-desmethylchlorpromazine sulphoxide. 3. Metabolites were separated by h.p.l.c. or g.l.c. prior to mass spectrometric analysis. The structures of the metabolites were confirmed by direct comparison of their mass spectra and chromatographic behaviours with those of authentic compounds. 4. Chlorpromazine N-oxide and any metabolite which retained the intact N-oxide function, such as chlorpromazine, N,S-dioxide, could not be identified in any of the extracts. 5. When 3H-chlorpromazine N-oxide was administered under the same conditions; approximately twice as much radioactivity was excreted in the faeces (52.1 +/- 9.7%) as in the urine (26.9 +/- 7.2%).

Synthesis and properties of haptens for the development of radioimmunoassays for thioridazine, mesoridazine, and sulforidazine.

For the separate development of radioimmunoassay procedures for thioridazine and its two major active metabolites, mesoridazine and sulforidazine, three haptens, respectively, 2-methylthio-, 2-methylsulfinyl-, and 2-methylsulfonyl-substituted 10-[2-[1-(2-carboxyethyl)-2-piperidinyl]ethyl]-10H-phenothiazine, were synthesized and characterized. Thioridazine hapten was coupled to bovine serum albumin, whereas the haptens for mesoridazine and sulforidazine were coupled to porcine thyroglobulin. The number of hapten residues per mole of carrier protein was determined in each case by an ultraviolet spectrophotometric method. Polyclonal antibodies to each hapten-protein conjugate were obtained in rabbits, and titers of the antisera were checked by evaluating their binding characteristics to the appropriate tritiated analyte. A hapten for the ring sulfoxide metabolite of thioridazine was also synthesized.