Concentration-related pharmacodynamic effects of thioridazine and its metabolites in humans

Abstract

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.

Structural and functional screening in human induced-pluripotent stem cell-derived cardiomyocytes accurately identifies cardiotoxicity of multiple drug types

“…*P b 0.05, **P b 0.01, and ***P b 0.0001. QTc prolongation, and Torsades de Pointes (Harrigan et al, 2004;Hartigan-Go et al, 1996;Thomas, 1994;Kelly, 1963), the structural toxicity shown is indicative of more direct damage on cardiomyocytes, which has been shown in previous nonclinical studies (Hull and Lockwood, 1986). Amiodarone, an antiarrhythmic, also showed significant structural effects, inducing lipids at 2 × its Cmax and increasing ROS and cell death at 17× its Cmax.…”

Pediatric Development of Glucuronidation: The Ontogeny of Hepatic UGT1A4

“…Phenothiazine drugs are largely metabolized by CYP2D6 (Llerena et al, 2000) with subsequent phase II metabolism. The major phase II metabolites commonly reported are sulfate conjugates (Hartigan-Go et al, 1996), but glucuronide conjugates have also been reported as the major urinary metabolite of phenothiazine drugs (Pieniaszek et al, 1999). The precise metabolic profile for trifluoperazine is unknown, but the contribution of UGT1A4 may not be the deciding factor in total hepatic clearance.…”

The effects of thioridazine on the QTc interval - cardiovascular safety in a South African setting

“…In the second study, Hartigan-Go et al 19 did a randomised, double-blind, three-period crossover study involving 9 healthy male subjects. They reported a dose-related prolongation of the to abnormal levels in almost one-quarter of subjects and to dangerous levels in 2 patients.…”