BINDING OF THIORIDAZINE AND THIORIDAZINE METABOLITES TO SERUM-PROTEINS IN PSYCHIATRIC-PATIENTS

A method is described for determining the free fraction of thioridazine and its side-chain sulfoxide, side-chain sulfone and ring sulfoxide metabolites in serum from thioridazine-treated patients. The method is based on equilibrium dialysis and gas chromatographic determination of the substances in the dialysate and in serum. The analyses are made at the actual serum concentrations and without the addition of extra substances. In sera from a group of thioridazine treated patients the mean free fraction of thioridazine was 0.15%, range 0.05-0.31%, and the corresponding values for thioridazine side-chain sulfoxide, side-chain sulfone, and ring sulfoxide were 1.66%, range 0.38-3.58%, 1.17%, range 0.36-2.20%, and 1.70%, range 0.61-3.49%, respectively. In experiments in vitro the percentage free fractions of thioridazine and its metabolites were found to increase with concentration. Since this applied, too, in the therapeutic concentration range, it may have clinical implications. However, it is extremely important to note that an increase in the concentration of any of these substances causes an increase in the percentage of all free fractions, which may indicate that they have a common binding site or sites. In the patients studied there was a close correlation between the percentage free fraction of all the substances at different concentrations of the parent compound. An albumin solution was found to bind thioridazine, but the free fraction was about 2%, i. e. much higher than the values found in serum, which indicates that thioridazine may be bound mainly to other serum proteins. Analysis of the percentage free fractions in the sera from patients with a number of clinical and physiological variables revealed few significant correlations. On average, however, female patients may have a larger free fraction of thioridazine and thioridazine side-chain sulfoxide than male patients. © 1978 Springer-Verlag.