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Cerebrospinal fluid concentrations of thioridazine and its main metabolites in psychiatric patients

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Summary

A gas chromatographic method for the determination of thioridazine and its metabolites has been developed for assay of the very low concentrations of these substances in the CSF. A certain degree of protein-binding in CSF was demonstrated by equilibrium dialysis, particularly of thioridazine, and to a lesser degree of its metabolites. In 48 psychiatric patients treated with thioridazine, 40 to 1000 mg/day, the mean total concentration of thioridazine in the CSF was 19.4 nmoles/l (range 4.0–47.3 nmoles/l), of thioridazine side-chain sulfoxide 30.5 nmoles/l (range 7.3–109.4 nmoles/l), of thioridazine side-chain sulfone 8.4 nmoles/l (range 1.4–19.6 nmoles/l), and of thioridazine ring sulfoxide 27.7 nmoles/l (range 4.0–71.0 nmoles/l). The free fraction of thioridazine in CSF averaged 49.1% (range 22.4–80.9%), and the corresponding values for thioridazine side-chain sulfoxide were 92% (range 72.5–109.7%) for thioridazine side-chain sulfone 68.8% (range 28.4–98.0%), and for thioridazine ring sulfoxide 81.7% (range 31.0–106.2%). The total CSF concentrations of thioridazine and thioridazine side-chain sulfone were significantly higher than their free serum concentrations whereas the total CSF concentration of thioridazine ring sulfoxide was significantly lower than its unbound serum concentration, and the total CSF concentration of the thioridazine side-chain sulfoxide did not differ from its free serum concentration. The unbound CSF concentration of thioridazine was also significantly higher than its unbound serum concentration (average 1.98 times higher; range 1.37–3.53). The unbound CSF concentration of the ring sulfoxide was only 43% (range 28–61%) of its unbound serum concentration (p <0.008), and the unbound concentrations of the other metabolites did not differ significantly between CSF and serum. Both the total and free CSF concentrations of thioridazine and its metabolites showed positive and usually quite significant correlations with the corresponding unbound concentrations in serum. The concentrations in CSF were much more closely related to the serum concentration than to the dose of thioridazine. The ratio of the total CSF concentration and the unbound serum concentration of thioridazine varied closely with the total CSF protein and albumin concentrations, but the ratio of the unbound CSF and serum concentrations did not show such a covariation. The concentrations of thioridazine in serum and CSF varied significantly with the age of the patients, but no other correlation with age could be demonstrated in the drug-related parameters. The sex of the patients appeared to influence the side-chain oxidation products, as the total CSF concentrations of the thioridazine side-chain sulfoxide and side-chain sulfone, as well as the free fraction in CSF of thioridazine side-chain sulfoxide, were significantly higher in women.

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References

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Nyberg, G., Axelsson, R. & Mårtensson, E. Cerebrospinal fluid concentrations of thioridazine and its main metabolites in psychiatric patients. Eur J Clin Pharmacol 19, 139–148 (1981). https://doi.org/10.1007/BF00568401

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  • DOI: https://doi.org/10.1007/BF00568401

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