CONCENTRATION-RELATED PHARMACODYNAMIC EFFECTS OF THIORIDAZINE AND ITSMETABOLITES IN HUMANS

Objective: To measure cardiac and other effects of thioridazine and re late these to the plasma concentration of the parent drug and its prin cipal metabolites. Methods: A double-blind, randomized-order crossover study involving nine healthy male subjects compared the effects of si ngle doses of thioridazine (10 mg and 50 mg) with placebo. Plasma conc entrations of thioridazine and its ring sulfoxide, side-chain sulfoxid e, and side-chain sulfone metabolites were measured, together with eff ects on the EGG, blood pressure, salivary flow, and a batch of psychom otor tests for 72 hours after administration. Results: Thioridazine, 5 0 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), i ncreased standing heart rate (7 beats/min [-1, 16 beats/min]; p < 0.05 ), impaired psychomotor function, and prolonged the JT (20 ms(1/2) [7, 34 ms(1/2)]; p < 0.05), QT(a)(22 ms(1/2)[8, 36 ms(1/2)]; p < 0.05), a nd QT,(22 ms(1/2) [11, 33 ms(1/2)]; p < 0.01) intervals, but had no ef fect on QT dispersion (-12 ms(1/2) [-31, 6 ms(1/2)]). Thioridazine, 10 mg, also significantly increased QT(c), but the effect was less marke d (9 ms(1/2) [-1, 19 ms(1/2)]; P < 0.05). Plasma thioridazine and meta bolite concentrations did not correlate significantly with these effec ts. Maximum effects on QT(c) occurred after peak concentrations of thi oridazine but before peak concentrations of the ring sulfoxide and sid e-chain sulfone metabolites. Conclusions: These data suggest that thio ridazine has dose-related effects on ventricular repolarization and th at the parent drug causes an important proportion of these effects, al though its metabolites may also contribute.