The metabolism of piperidine-type phenothiazine antipsychotic agents. III. Mesoridazine in dog, human and rat.

1. The metabolism of mesoridazine was studied in female rats (20 mg/kg, oral), female dogs (50 mg over 30 h, oral) and adult male volunteers (25 mg, oral). 2. Solvent extracts of urines from each species were directly analysed by h.p.l.c.-mass spectrometry with a plasmaspray interface. In the case of phenolic metabolites the urinary extracts were derivatized with a silylating reagent (with and without prior enzymic hydrolysis) prior to analysis. The structures of metabolites, with the exceptions of mesoridazine N-oxide and phenols, were confirmed by comparison of their chromatographic behaviours and mass spectra with those of authentic standards. 3. Compounds identified in the urine of all three species were mesoridazine, sulforidazine, mesoridazine ring sulphoxide, sulforidazine ring sulphoxide, N-desmethylmesoridazine ring sulphoxide, the lactam of sulforidazine ring sulphoxide and phenolic derivatives of mesoridazine and sulforidazine. Whereas the unconjugated phenolic metabolite of sulforidazine was present in urine of all three species, the conjugated form was identified only in dog and rat urines. Also, the unconjugated phenolic metabolite of mesoridazine was identified only in the urine of dog and human, but rat urine contained only the conjugated form. 4. Other metabolites found were: the lactam of mesoridazine (rat), the lactam of mesoridazine ring sulphoxide (rat and human), mesoridazine N-oxide (human) and sulforidazine N-oxide (dog and human). 5. Mesoridazine and six of its metabolites present in urines of human, rat and dog were quantified by a h.p.l.c.-u.v. method. The mean total excretion of measured analytes in human, rat and dog were 6.3, 2.6 and 29.1%, respectively. The excretion of the lactam of sulforidazine ring sulphoxide was greater in human (0.4%) and rat (0.2%) than dog (0.02%). Moreover, the urinary excretion of the lactam of mesoridazine ring sulphoxide in human and rat constituted 0.4% and 0.2%, respectively. Of the three lactams found in rat the lactam of mesoridazine was present in the least amount (0.05%). 6. Interspecies comparison of the lactam metabolites indicated that both qualitatively and quantitatively human more closely resembled rat than dog. On the other hand, N-oxide metabolites were detected in human and dog but not in rat.

Light-induced racemization: artifacts in the analysis of the diastereoisomeric pairs of thioridazine 5-sulfoxide in the plasma and urine of patients treated with thioridazine.

The ring sulfoxidation of thioridazine (THD), a widely used neuroleptic agent, yields two diastereoisomeric pairs, fast- and slow-eluting (FE and SE) thioridazine 5-sulfoxide (THD 5-SO). Until now, studies in which concentrations of these metabolites were measured in THD-treated patients have revealed no significant differences in their concentrations. Preliminary experiments in our laboratory had shown that sunlight and, to a lesser extent, dim daylight led to racemization and probably also to photolysis of the diastereoisomeric pairs as measured by high-performance liquid chromatography. Similar results were also obtained with direct UV light (UV lamp). In appropriate light-protected conditions, THD, northioridazine, mesoridazine, sulforidazine, and FE and SE THD 5-SO were measured in 11 patients treated with various doses of THD for at least 1 week. Significantly higher concentrations of the FE stereoisomeric pair were found. The concentration ratios THD 5-SO (FE)/THD 5-SO (SE) ranged from 0.89 to 1.75 in plasma and from 1.15 to 2.05 in urine. Because it is known that the ring sulfoxide contributes to the cardiotoxicity of the drug even more potently than the parent compound does, these results justify further studies to determine whether there is stereoselectivity in the cardiotoxicity of THD 5-SO.

Sulphoxide metabolites of thioridazine in man.

Chromatograms of urine extracts from patients taking thioridazine contain several different sulphoxide metabolites. Some of these have not hitherto been described or identified. Two of the unknown metabolites appear, from chemical tests and mass spectrometry, to be isomers of the already known thioridazine ring-sulphoxide and sulphoridazine ring-sulphoxide from which they can be produced by treatment with trifluoroacetic anhydride. Two others appear, by similar identification tests and i.r. analysis, to be lactams of mesoridazine ring-sulphoxide and of sulphoridazine ring-sulphoxide.

Combined ultraviolet-fluorescence detection in high-pressure liquid chromatography of pharmaceuticals.

The use of combined UV-fluorescence detection for the evaluation of incompletely resolved compounds and trace components in the presence of large quantities of major components is described, analysis for thioridazine and some of its oxidation products by high-pressure liquid chromatography being chosen as a practical example. Mesoridazine and the ring oxide of thioridazine have been determined quantitatively with relative standard deviations (n = 6) of 2.0 and 3.6%, respectively, at concentrations below 0.1 mug per injection. Resolution of the two components is difficult and, in this instance, unnecessary. By a similar approach, it was possible to determine the highly fluoresecent sulforidazine at a concentration of 0.4% of the thioridazine with 6.2 mug of thioridazine injected. A relative standard deviation of 5% was attainable at this concentration. Fluorescence detection limits for mesoridazine and sulforidazine at a signal-to-noise ratio of 4:1 are between 5 and 10 ng per injection; this corresponds to about 0.1% of the active substance for the above example.

Absorption and excretion of thioridazine and mesoridazine in man.

Tritium labeled thioridazine and mesoridazine were given to four schizophrenic subjects to determine if differences in reported clinical potency of these two drugs could be explained by different rates of absorption and excretion. Mesoridazine was found to have earlier peak blood levels and lower fecal excretion. However, the blood and fecal differences were too small to be an adequate explanation for the differences in clinical potency suggesting that the rate of metabolic degradation is a more likely explanation for the potency difference. Thioridazine differs from other phenothiazines by containing two sulfur atoms. Thioridazine is metabolized by oxidative demethylation, oxidation at both sulfur atoms to sulfoxides and sulfones and by hydroxylation in the ring followed by glucuronide formation. Monosufoxides, disulfoxide and disufone have been found in the urine and bile of rats after thioridazine administration by inverse isotope dilution analysis. Neither the ring sulfoxide nor the disulfone show significant pharmacological activity, but activity is shown by the side chain monosulfoxide, mesoridazine. In fact it has been postulated that mesoridazine is the active form of thioridazine. Mesoridazine when compared on an equal dose basis to thioridazine is more potent in anti-emotional and hypotensive effects and produces more extrapyramidal symptoms. Since oxidation of the ring sulfur would be expected to decrease potency, it has been theorized that a portion of thioridazine is oxidized within the ring prior to the oxidation of the side chain sulfur atom thus effectively decreasing the potential activity of thioridazine. Thioridazine studies in rats have shown greater excretion in the urine and bile of the side chain sulfoxide than of the ring sulfoxide or of unchanged thioridazine. The difference in potency of these two compounds could alternatively be a result of differences in absorption, reabsorption after biliary excretion or the rate of urinary excretion. The metabolic pathways of mesoridazine in the human are essentially unknown. Because of this, we thought it worthwhile to determine if the difference in potency between thioridazine and mesoridazine is also related to differences in the rate of excretion and absorption. Because phenothiazines are found in extremely low plasma concentrations, we used radioactive compounds to perform this study.