Plasma Concentrations of Thioridazine Metabolites and ECG Abnormalities

doi:10.1002/jps.2600670208

Journal of Pharmaceutical Sciences

Volume 67, Issue 2, February 1978, Pages 155-157

https://doi.org/10.1002/jps.2600670208 Get rights and content

Abstract

Five acute schizophrenic patients were given a standard thioridazine dose (4 mg/kg/day po). Their plasma concentrations of thioridazine and its metabolites were determined by GLC, and their ECG’s were recorded routinely. In four of the five patients, abnormal ECG’s (malformation of the T-wave or lengthening of the repolarization time) were found whenever plasma concentrations of the thioridazine ring sulfoxide were elevated. No relationship could be detected between the appearance of ECG abnormalities and the concentrations of thioridazine and its other metabolites.

REFERENCES (18)

L.A. Gottschalk et al.
Comp. Psychiat.
(1975)
E.C. Dinovo et al.
J. Pharm. Sci.
(1976)
R.G. Muusze et al.
J. Chromatogr.
(1973)
A.G. Kelly et al.
Can. Med. Assoc. J.
(1963)
J.R. Huston et al.
J. Am. Med. Assoc.
(1966)
R.J. Rosenquist et al.
Minn. Med.
(1971)
C. Thornton et al.
Dis. Neru. Syst.
(1971)
D.M. Gallant et al.
Curr. Ther. Res.
(1972)
J.M. Samet et al.
J. Clin. Pharmacol.
(1974)

There are more references available in the full text version of this article.

Cited by (34)

A phase 1 trial evaluating thioridazine in combination with cytarabine in patients with acute myeloid leukemia
2018, Blood Advances
Citation Excerpt :
However, it is noteworthy that following TDZ discontinuation, patient 3 continued to show significant QTc prolongation (supplemental Figure 1). Moreover, after plasma concentrations of TDZ and TDZ 5-sulfoxide (the metabolite associated with cardiotoxicity19-22) were reduced to undetectable levels, frequent QTc prolongation events continued to be noted on serial ECGs (supplemental Figure 1). These QTc changes in patient 3 were not associated with fluctuations in magnesium or potassium levels.
We completed a phase 1 dose-escalation trial to evaluate the safety of a dopamine receptor D2 (DRD2) antagonist thioridazine (TDZ), in combination with cytarabine. Thirteen patients 55 years and older with relapsed or refractory acute myeloid leukemia (AML) were enrolled. Oral TDZ was administered at 3 dose levels: 25 mg (n = 6), 50 mg (n = 4), or 100 mg (n = 3) every 6 hours for 21 days. Intermediate-dose cytarabine was administered on days 6 to 10. Dose-limiting toxicities (DLTs) included grade 3 QTc interval prolongation in 1 patient at 25 mg TDZ and neurological events in 2 patients at 100 mg TDZ (gait disturbance, depressed consciousness, and dizziness). At the 50-mg TDZ dose, the sum of circulating DRD2 antagonist levels approached a concentration of 10 μM, a level noted to be selectively active against human AML in vitro. Eleven of 13 patients completed a 5-day lead-in with TDZ, of which 6 received TDZ with hydroxyurea and 5 received TDZ alone. During this period, 8 patients demonstrated a 19% to 55% reduction in blast levels, whereas 3 patients displayed progressive disease. The extent of blast reduction during this 5-day interval was associated with the expression of the putative TDZ target receptor DRD2 on leukemic cells. These preliminary results suggest that DRD2 represents a potential therapeutic target for AML disease. Future studies are required to corroborate these observations, including the use of modified DRD2 antagonists with improved tolerability in AML patients. This trial was registered at www.clinicaltrials.gov as #NCT02096289.
Stereoselective analysis of thioridazine-2-sulfoxide and thioridazine-5-sulfoxide: An investigation of rac-thioridazine biotransformation by some endophytic fungi
2008, Journal of Pharmaceutical and Biomedical Analysis
The purpose of this study was to develop a method for the stereoselective analysis of thioridazine-2-sulfoxide (THD-2-SO) and thioridazine-5-sulfoxide (THD-5-SO) in culture medium and to study the biotransformation of rac-thioridazine (THD) by some endophytic fungi. The simultaneous resolution of THD-2-SO and THD-5-SO diastereoisomers was performed on a CHIRALPAK^® AS column using a mobile phase of hexane:ethanol:methanol (92:6:2, v/v/v) + 0.5% diethylamine; UV detection was carried out at 262 nm. Diethyl ether was used as extractor solvent. The validated method was used to evaluate the biotransformation of THD by 12 endophytic fungi isolated from Tithonia diversifolia, Viguiera arenaria and Viguiera robusta. Among the 12 fungi evaluated, 4 of them deserve prominence for presenting an evidenced stereoselective biotransformation potential: Phomopsis sp. (TD2) presented greater mono-2-sulfoxidation to the form (S)-(SE) (12.1%); Glomerella cingulata (VA1) presented greater mono-5-sulfoxidation to the forms (S)-(SE) + (R)-(FE) (10.5%); Diaporthe phaseolorum (VR4) presented greater mono-2-sulfoxidation to the forms (S)-(SE) and (R)-(FE) (84.4% and 82.5%, respectively) and Aspergillus fumigatus (VR12) presented greater mono-2-sulfoxidation to the forms (S)-(SE) and (R)-(SE) (31.5% and 34.4%, respectively).
The role of lysosomes in the cellular distribution of thioridazine and potential drug interactions
1999, Toxicology and Applied Pharmacology
The purpose of the present study was to investigate the contribution of lysosomal trapping to the total tissue uptake of thioridazine and to potential drug distribution interactions between thioridazine and tricyclic antidepressants (imipramine, amitriptyline) or selective serotonin reuptake inhibitors (SSRIs; fluoxetine, sertraline). The experiment was carried out on slices of various rat tissues as a system with intact lysosomes. Thioridazine and antidepressants (5 μM) were incubated separately or jointly with the tissue slices in the absence or presence of “lysosomal inhibitors,” i.e., ammonium chloride or monensin. The results show that the contribution of lysosomal trapping to the total tissue uptake of thioridazine is as important as phospholipid binding. A high degree of dependence of thioridazine tissue uptake on the lysosomal trapping is the cause of substantial distributive interactions between thioridazine and the investigated antidepressants at the level of cellular distribution. Thioridazine and the antidepressants, both tricyclic and SSRIs, mutually decreased their tissue uptake. The potency of antidepressants to decrease thioridazine uptake was similar to that of lysosomal inhibitors. In general, the observed interactions between thioridazine and antidepressants occurred only in those tissues in which thioridazine showed lysosomotropism (the lungs, liver, kidneys, brain, and muscles) but were not observed in the presence of ammonium chloride. The above finding provides evidence that the interactions proceeded at the level of lysosomal trapping. In the adipose tissue and heart no lysosomal trapping of thioridazine was detected and those tissues were not the site of such an interaction. Since the organs and tissues involved in the distributive interactions constitute a major part of the organism and take up most of the total drug in the body, the interactions occurring in them may cause a substantial shift of the drugs to organs and tissues poor in lysosomes, e.g. the heart and muscles. An in vivo study into the thioridazine–imipramine interaction showed that joint administration of the drugs under study (10 mg/kg ip) increased drug concentration ratios of lysosome-poor tissue/plasma and lysosome-poor/lysosome-rich tissue. Considering serious side effects of thioridazine and tricyclic antidepressants (cardiotoxicity, anticholinergic activity), the thioridazine–antidepressant combinations studied should be approached with respect to the appropriate dose adjustment.
Determination of the serum concentrations of thioridazine and its main metabolites using a solid-phase extraction technique and high-performance liquid chromatography
1990, Journal of Chromatography B: Biomedical Sciences and Applications
Convenient oxidation of phenothiazine salts to their sulfoxides with aqueous nitrous acid
1989, Journal of Pharmaceutical Sciences
Cardiotoxicity of thioridazine and two stereoisomeric forms of thioridazine 5-sulfoxide in the isolated perfused rat heart
1986, Toxicology and Applied Pharmacology
The cardiotoxic potential of the phenothiazine neuroleptic thioridazine and five of its metabolites, including two stereoisomeric forms of thioridazine 5-sulfoxide (ring sulfoxide), was characterized in the isolated perfused rat heart. Hearts from male Sprague-Dawley rats were perfused using a modified Langendorff technique. After a 30-min control period, hearts were perfused for 30 min with 15 or 30 μm thioridazine, racemic and isomeric forms of thioridazine 5-sulfoxide, or thioridazine 2-sulfoxide. Thioridazine disulfoxide, thioridazine 2-sulfone, and desmethylthioridazine 2-sulfoxide were perfused at 15 μm. Thioridazine (15 μm) severely reduced contractile tension and the rate of tension development ( $dT dt$ ), transiently increased coronary flow rate but prolonged conductance through the AV node. No arrhythmias were seen. At 30 μm, ventricular premature contractions and irregular rhythms occurred, progressing to asystole. Thioridazine 5-sulfoxide was arrhythmogenic at 15 and 30 μm. Atrial premature contractions and paroxysmal atrial tachycardia progressed to second degree AV block. Contractile tension and $dT dt$ declined although not as quickly when compared to thioridazine. Each isomeric form of thioridazine 5-sulfoxide was also cardiotoxic at 15 and 30 μm. There were minor differences in the onset and degree of toxicity but the overall results did not suggest a stereoselective effect. Lactic dehydrogenase and aspartate aminotransferase concentrations were unchanged after thioridazine 5-sulfoxide perfusion indicating no direct tissue damage. Thioridazine 5-sulfoxide induced arrhythmias could not be prevented or reversed by treatment with adrenergic agonists. They were reversible upon washout, however. The other metabolites were not arrhythmogenic at 15 μm. Racemic thioridazine 5-sulfoxide appears to be qualitatively and quantitatively more arrhythmogenic than thioridazine, an action that does not appear to be stereoselective.

View all citing articles on Scopus

View full text

Research ArticlesPlasma Concentrations of Thioridazine Metabolites and ECG Abnormalities

Abstract

Comp. Psychiat.

J. Pharm. Sci.

J. Chromatogr.

Can. Med. Assoc. J.

J. Am. Med. Assoc.

Minn. Med.

Dis. Neru. Syst.

Curr. Ther. Res.

J. Clin. Pharmacol.

Research Articles
Plasma Concentrations of Thioridazine Metabolites and ECG Abnormalities