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.