Comparison of the effects of thioridazine and mesoridazine on the QT interval in healthy adults after single oral doses.

We compared the effects of single doses of thioridazine and mesoridazine on the heart rate-corrected QT (QTc) interval in healthy adult volunteers. QTc intervals and plasma concentrations of thioridazine, mesoridazine, and metabolites were measured after single oral doses of thioridazine hydrochloride 50 mg, mesoridazine besylate 50 mg, or placebo in a double-blind, crossover study. Mean maximum increases in the QTc interval following thioridazine (37.3+/-4.1 ms, P=0.023) and mesoridazine (46.6+/-7.4 ms, P=0.021) were similar and significantly greater than following placebo (12.9+/-8.1 ms). The area under the effect-time curve over 8 h following drug administration was similar between the two drugs (129.3+/-22.1 vs 148.3+/-43.0 ms h). In conclusion, thioridazine and mesoridazine are associated with similar effects on the QTc interval.

Pharmacokinetic interaction of fluvoxamine and thioridazine in schizophrenic patients.

This study investigated to what extent fluvoxamine affects the pharmacokinetics of thioridazine (THD) in schizophrenic patients under steady-state conditions. Concentrations of THD, mesoridazine, and sulforidazine were measured in plasma samples obtained from 10 male inpatients, aged 36 to 78 years, at three different time points: A, during habitual monotherapy with THD at 88 +/-54 mg/day; B, after addition of a low dosage of fluvoxamine (25 mg twice a day) for 1 week; and C, 2 weeks after fluvoxamine discontinuation. After the addition of fluvoxamine, THD concentrations relative to time point A significantly increased approximately threefold from 0.40 to 1.21 micromol/L (225%) (p < 0.002), mesoridazine concentrations increased from 0.65 to 2.0 micromol/L (219%) (p < 0.004), and sulforidazine levels increased from 0.21 to 0.56 micromol/L (258%) (p < 0.004). The THD-mesoridazine and THD-sulforidazine ratios remained unchanged during the study. Mean plasma THD, mesoridazine, and sulforidazine levels decreased at time point C, but despite fluvoxamine discontinuation for 2 weeks, three patients continued to exhibit elevated concentrations of THD and its metabolites. In conclusion, fluvoxamine markedly interferes with the metabolism of THD, probably at the CYP2C19 and/or CYP1A2 enzyme level. Therefore, clinicians should be aware of the potential for a clinical drug interaction between both compounds, and careful monitoring of THD levels is valuable to prevent the accumulation of the drug and resulting toxicity.

Pharmacokinetics of thioridazine and its metabolites in blood plasma and the brain of rats after acute and chronic treatment.

This study was aimed at investigation of the pharmacokinetics of thioridazine and its metabolites after a single and repeated administrations. Male Wistar rats received thioridazine as a single dose (10 mg/kg i.p.) or they were treated chronically with the neuroleptic (10 mg/kg i.p., twice a day for two weeks). Plasma and brain concentrations of thioridazine and its metabolites (N-desmethylthioridazine, mesoridazine, sulforidazine, and the ring sulfoxide) were determined using the HPLC method. The obtained data showed that sulfoxidation in position 2 of the thiomethyl substituent and in the thiazine ring are main metabolic pathways of thioridazine, and showed that, in contrast to humans, in the rat N-desmethylthioridazine is formed in appreciable amount. The biotransformation of thioridazine was rather fast yielding plasma peak concentrations of metabolites lower than that of the parent compound. The maximum concentrations of thioridazine and its metabolites in the brain appeared later than in plasma. The peak concentrations and AUC values of thioridazine and its metabolites were higher in the brain than in plasma and this corresponded well with their longer half-lives in the brain as compared to plasma. The drug was not taken up by the brain as efficiently as other phenothiazines. Chronic treatment with thioridazine produced significant increases (with the exception of thioridazine ring sulfoxide) in the plasma concentrations of the parent compound and its metabolites which was accompanied with the prolongation of their plasma half-lives. The observed plasma levels of thioridazine were within 'therapeutic range' while the concentrations of its metabolites were relatively lower as compared to those observed in psychiatric patients. The increased plasma concentrations of thioridazine and its metabolites observed in plasma after chronic treatment were not followed by parallel changes in the brain.

Identification of lactams as in vitro metabolites of piperidine-type phenothiazine antipsychotic drugs.

The metabolism of the piperidine-type phenothiazine antipsychotic agents thioridazine, mesoridazine and sulforidazine was studied in vitro with 10,000 g liver supernatants obtained from rats and dogs. After incubations at 37 degrees C for different time intervals, the incubates were extracted with dichloromethane and the isolated compounds analyzed by HPLC, direct probe MS and on-line HPLC-MS. Five lactam metabolites of these three drugs were unequivocally identified in the rat in vitro system, but none was found in dog preparations; at least one lactam metabolite was identified for each drug in the rat. The lactams of thioridazine and thioridazine ring sulfoxide were characterized as metabolites of thioridazine for the first time in any system. The other three lactam metabolites, namely the lactams of mesoridazine, sulforidazine and mesoridazine ring sulfoxide, were found in vitro for the first time, although they have been previously reported as in vivo metabolites of these drugs. The results indicate that rat would be a more suitable animal model than dog for further studies on the formation of lactam metabolites of these drugs.

Stepwise determination of multicompartment disposition and absorption parameters from extravascular concentration-time data. Application to mesoridazine, flurbiprofen, flunarizine, labetalol, and diazepam.

When disposition is monoexponential, extravascular concentration-time (C, t) data yield both disposition and absorption parameters, the latter via the Wagner-Nelson method or deconvolution which are equivalent. Classically, when disposition is multiexponential, disposition parameters are obtained from intravenous administration and absorption data are obtained from extravascular C, t data via the Loo-Riegelman or Exact Loo-Riegelman methods or via deconvolution. Thus, in multiexponential disposition one assumes no intrasubject variation in disposition, a hypothesis that has not been proven for most drugs. Based on the classical two- and three-compartment open models with central compartment elimination, and using postabsorptive extravascular C, t data only, we have developed four equations to estimate k10 when disposition is biexponential and two other equations to estimate k10 when disposition is triexponential. The other disposition rate constants are readily obtained without intravenous data. We have analyzed extravascular data of flurbiprofen (12 sets), mesoridazine (20 sets), flunarizine (5 sets), labetalol (9 sets), and diazepam (4 sets). In the case of diazepam intravenous C, t data were also available for analysis. After disposition parameters had been estimated from the extravascular data the Exact Loo-Riegelman method with the Proost modification was applied to the absorptive extravascular data to obtain AT/VP as a function of time. These latter data for each subject and each drug studied were found to be fitted by a function indicating either simple first-order absorption, two consecutive first-order processes, or zero-order absorption. After absorption and disposition parameters had been estimated, for each set of extravascular data analyzed, a reconstruction trend line through the original C, t data was made. The new methods allow testing of the hypothesis of constancy of disposition with any given drug. There is also a need for new methods of analysis since the majority of drugs have no marketed intravenous formulation, hence the classical methods cannot be applied.

Plasma levels of thioridazine and metabolites are influenced by the debrisoquin hydroxylation phenotype.

The pharmacokinetics of thioridazine and its metabolites were studied in 19 healthy male subjects: 6 slow and 13 rapid hydroxylators of debrisoquin. The subjects received a single 25 mg oral dose of thioridazine, and blood samples were collected during 48 hours. Concentrations of thioridazine and metabolites in serum were measured by HPLC. Slow hydroxylators of debrisoquin obtained higher serum levels of thioridazine with a 2.4-fold higher Cmax and a 4.5-fold larger AUC(0-infinity) associated with a twofold longer half-life compared with that of rapid hydroxylators. The side-chain sulphoxide (mesoridazine) and sulphone (sulphoridazine), which are active metabolites, appeared more slowly in serum and had lower Cmax values, but comparable AUC. The thioridazine ring-sulphoxide attained higher Cmax and 3.3-fold higher AUC in slow hydroxylators than in rapid hydroxylators of debrisoquin. Thus the formation of mesoridazine from thioridazine and the 4-hydroxylation of debrisoquin seem to be catalyzed by the same enzyme, whereas the formation of thioridazine ring-sulphoxide is probably formed mainly by another enzyme.

S-oxidation of thioridazine to psychoactive metabolites: an oral dose-proportionality study in healthy volunteers.

Thioridazine has two major active metabolites, which are formed from S-oxidation of its 2-methylthio group; the sulphoxide, mesoridazine, and the sulphone, sulforidazine. Dose proportionality of the three compounds was investigated for the first time in 11 males after administration of three single oral doses (25, 50, and 100 mg) of thioridazine hydrochloride separated in each case by two weeks. Based on the plasma concentrations of the three analytes over 72 h following each dose, large intersubject variabilities in such parameters as AUCot and Cmax were observed for each of the three compounds. The relationships between dose and parameters such as AUCot and Cmax for each analyte were described by an equation for a straight line (r2 greater than or equal to 0.8). However, the mean apparent distribution and elimination rate constants for thioridazine and mesoridazine and the mean apparent oral clearance for thioridazine decreased significantly with increasing dose, suggesting non-linearity in the elimination of thioridazine at high dose.

Absorption and excretion of thioridazine and mesoridazine in man.

Tritium labeled thioridazine and mesoridazine were given to four schizophrenic subjects to determine if differences in reported clinical potency of these two drugs could be explained by different rates of absorption and excretion. Mesoridazine was found to have earlier peak blood levels and lower fecal excretion. However, the blood and fecal differences were too small to be an adequate explanation for the differences in clinical potency suggesting that the rate of metabolic degradation is a more likely explanation for the potency difference. Thioridazine differs from other phenothiazines by containing two sulfur atoms. Thioridazine is metabolized by oxidative demethylation, oxidation at both sulfur atoms to sulfoxides and sulfones and by hydroxylation in the ring followed by glucuronide formation. Monosufoxides, disulfoxide and disufone have been found in the urine and bile of rats after thioridazine administration by inverse isotope dilution analysis. Neither the ring sulfoxide nor the disulfone show significant pharmacological activity, but activity is shown by the side chain monosulfoxide, mesoridazine. In fact it has been postulated that mesoridazine is the active form of thioridazine. Mesoridazine when compared on an equal dose basis to thioridazine is more potent in anti-emotional and hypotensive effects and produces more extrapyramidal symptoms. Since oxidation of the ring sulfur would be expected to decrease potency, it has been theorized that a portion of thioridazine is oxidized within the ring prior to the oxidation of the side chain sulfur atom thus effectively decreasing the potential activity of thioridazine. Thioridazine studies in rats have shown greater excretion in the urine and bile of the side chain sulfoxide than of the ring sulfoxide or of unchanged thioridazine. The difference in potency of these two compounds could alternatively be a result of differences in absorption, reabsorption after biliary excretion or the rate of urinary excretion. The metabolic pathways of mesoridazine in the human are essentially unknown. Because of this, we thought it worthwhile to determine if the difference in potency between thioridazine and mesoridazine is also related to differences in the rate of excretion and absorption. Because phenothiazines are found in extremely low plasma concentrations, we used radioactive compounds to perform this study.