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Objective: To measure cardiac and other effects of thioridazine and relate these to the plasma concentration of the parent drug and its principal metabolites., Methods: A double-blind, randomized-order crossover study involving nine healthy male subjects compared the effects of single doses of thioridazine (10 mg and 50 mg) with placebo. Plasma concentrations of thioridazine and its ring sulfoxide, side-chain sulfoxide, and side-chain sulfone metabolites were measured, together with effects on the ECG, blood pressure, salivary flow, and a batch of psychomotor tests for 72 hours after administration., Results: Thioridazine, 50 mg, reduced standing systolic blood pressure (mean peak changes from baseline [95% CI] -32 mm Hg [-55, 10 mm Hg]; p < 0.01 versus placebo) and diastolic blood pressure (-14 mm Hg [-26, -2 mm Hg]; p < 0.05), increased standing heart rate (7 beats/min [-1, 16 beats/min]; p < 0.05), impaired psychomotor function, and prolonged the JT (20 ms1/2 [7, 34 ms1/2]; p < 0.05), QTa (22 ms1/2 [8, 36 ms1/2]; p < 0.05), and QTc (22 ms1/2 [11, 33 ms1/2]; p < 0.01) intervals, but had no effect on QT dispersion (-12 ms1/2 [-31, 6 ms1/2]). Thioridazine, 1.0 mg, also significantly increased QTc, but the effect was less marked (9 ms1/2 [-1, 19 ms1/2]; p < 0.05). Plasma thioridazine and metabolite concentrations did not correlate significantly with these effects. Maximum effects on QTc occurred after peak concentrations of thioridazine but before peak concentrations of the ring sulfoxide and side-chain sulfone metabolites., Conclusions: These data suggest that thioridazine has dose-related effects on ventricular repolarization and that the parent drug causes an important proportion of these effects, although its metabolites may also contribute.

Thioridazine, thioridazine side chain sulfoxide, side chain sulfone and ring sulfoxide were each given to two dogs in incremental doses. Profound changes in cardiac output and blood pressure were seen only in the dogs receiving the ring sulfoxide. Although all four drugs increased the QRS and Q-Tc interval, ventricular arrhythmias and "torsades de pointes" were seen only in dogs receiving the ring sulfoxide. Total plasma concentrations of thioridazine ring sulfoxide were in the same range as those seen in some patients on thioridazine therapy although the free concentrations were higher. Thioridazine ring sulfoxide appears to be the most toxic metabolite of thioridazine.

The binding constants of the binding between thioridazine and its metabolites, side-chain sulfoxide, side-chain sulfone and ring sulfoxide, on the one hand, and the plasma proteins, alpha 1-acid glycoprotein, albumin and total serum proteins, on the other, were determined. The binding constants between the drug substances and alpha 1-acid glycoprotein were found to be about a thousand times higher than the binding constants between the drug substances and albumin. The binding constants of whole serum were close to those of alpha 1-acid glycoprotein. Analysis of the binding data indicated competition between thioridazine and its metabolites. A number of drug substances were screened for possible binding interaction with thioridazine and its metabolites. Tricyclic antidepressants and propranolol significantly increased the free concentration of thioridazine. Also salicyclic acid and the plasticizing agent, TBEP, had this effect.

The concentrations of thioridazine and its main metabolites in erythrocytes from 61 thioridazine-treated patients were determined by gas-liquid chromatography. The mean and range of the erythrocyte concentrations, expressed as percentage of the corresponding plasma concentrations, were: thioridazine, 5.1% (2.0-10.6); side-chain sulfoxide, 5.6% (1.6-10.4); side-chain sulfone, 3.3% (1.1-6.8); ring sulfoxide 2.7% (0.8-4.9). The erythrocyte and plasma concentrations were significantly correlated. The erythrocyte/plasma concentration ratios, all the erythrocyte concentrations, but none of the plasma concentrations except ring sulfoxide were significantly positively correlated to the dose of thioridazine. The erythrocyte/plasma concentration ratio was not correlated to age. In vitro experiments indicated no clinically relevant erythrocyte-mediated oxidation of thioridazine.

The relationships between, on the one hand, the unbound plasma concentrations of thioridazine and thioridazine metabolites and, on the other, the total plasma concentrations and the red blood cell concentrations were studied in vitro. The relationships between the unbound and total plasma concentrations were curvilinear, while those between the unbound concentrations and the red blood cell concentrations within a broad range were closer to rectilinear. Profound changes were seen in the relationship between unbound and total plasma concentrations at varying concentrations of alpha 1-acid glycoprotein, while the rectilinear relationship between the unbound plasma concentrations and the red blood cell concentrations remained essentially unchanged.

The blood chemistry and clinical pharmacokinetics of thioridazine and its metabolites, side-chain sulphoxide, side-chain sulphone and ring sulphoxide, were studied in 31 alcoholics and were compared with values in 17 thioridazine-treated controls without alcoholism. Pathological blood chemistry values, including abnormal liver function and protein concentrations, were common among the alcoholics. In relation to dosage, the majority had a low serum concentration of thioridazine and at a given concentration of thioridazine they had high serum concentrations of its metabolites. Positive intercorrelations were found between pathological liver function tests, prolonged serum half-life and increased serum concentration of thioridazine. The free fractions of thioridazine, side-chain sulphoxide and ring sulphoxide were significantly higher and those of the side-chain sulphone lower in the alcoholics than in the controls. The free fractions of side-chain and ring sulphoxide were significantly increased in patients with a low concentration of alpha 1-acid glycoprotein.

Neuroleptic drug concentrations at the receptor sites are likely to be reflected more closely by the unbound than by the total plasma concentrations. The aim of this study was to establish whether or not the unbound plasma concentrations of thioridazine and its main nonconjugated metabolites show a stronger correlation to the red blood cell (RBC) concentration than to the total plasma concentration of the drug. The total and unbound plasma concentrations and the RBC concentrations of thioridazine and its metabolites were therefore determined in thioridazine-treated patients. "Calculated unbound concentration values" were derived from the determined total concentrations of the drug, the concentrations of drug-binding proteins, and previously determined kappa values. Since the RBC concentrations showed the best correlation to the unbound plasma values, they may be a more accurate tool than the total plasma concentrations for monitoring thioridazine treatment. The determined unbound plasma concentrations were better correlated to the calculated unbound concentrations than to the total plasma concentrations. The total plasma concentrations, but neither the unbound plasma nor the RBC concentrations, were significantly correlated to the concentrations of the drug-binding protein alpha 1-acid glycoprotein. Radioreceptor assay values were strongly correlated to the weighted sum of the total and unbound plasma concentrations of thioridazine and its metabolites.