Reduced emergence of isoniazid resistance with concurrent use of thioridazine against acute murine tuberculosis.

The repurposing of existing drugs is being pursued as a means by which to accelerate the development of novel regimens for the treatment of drug-susceptible and drug-resistant tuberculosis (TB). In the current study, we assessed the activity of the antipsychotic drug thioridazine (TRZ) in combination with the standard regimen in a well-validated murine TB model. Single-dose and steady-state pharmacokinetic studies were performed in BALB/c mice to establish human-equivalent doses of TRZ. To determine the bactericidal activity of TRZ against TB in BALB/c mice, three separate studies were performed, including a dose-ranging study of TRZ monotherapy and efficacy studies of human-equivalent doses of TRZ with and without isoniazid (INH) or rifampin (RIF). Therapeutic efficacy was assessed by the change in mycobacterial load in the lung. The human-equivalent dose of thioridazine was determined to be 25 mg/kg of body weight, which was well tolerated in mice. TRZ was found to accumulate at high concentrations in lung tissue relative to serum levels. We observed modest synergy during coadministration of TRZ with INH, and the addition of TRZ reduced the emergence of INH-resistant mutants in mouse lungs. In conclusion, this study further illustrates the opportunity to reevaluate the contribution of TRZ to the sterilizing activity of combination regimens to prevent the emergence of drug-resistant M. tuberculosis.

Thioridazine pharmacokinetic-pharmacodynamic parameters "Wobble" during treatment of tuberculosis: a theoretical basis for shorter-duration curative monotherapy with congeners.

Phenothiazines are being repurposed for treatment of tuberculosis. We examined time-kill curves of thioridazine and first-line drugs against log-growth-phase and semidormant bacilli under acidic conditions and nonreplicating persistent Mycobacterium tuberculosis. While both the potency and the efficacy of first-line drugs declined dramatically as M. tuberculosis replication rates decreased, those of thioridazine improved. The mutation prevalence to 3 times the thioridazine MIC was <1 × 10(-11), better than for ≥2 first-line drugs combined. Hollow fiber system studies revealed that the relationship between sterilizing effect and pharmacodynamic indices (PDI) was characterized by an r(2) of 0.88 for peak/MIC, an r(2) of 0.47 for the area under the concentration-time curve (AUC) to MIC, and an r(2) of 0.14 for the cumulative percentage of a 24-h period that the drug concentration exceeds the MIC under steady-state pharmacokinetic conditions (%TMIC) at the end of the first week. However, the PDI linked to effect "wobbled" as the duration of therapy increased, so that by the fourth week the r(2) was 0.88 for AUC/MIC, 0.78 for %TMIC, and 0.72 for peak/MIC. This "wobble" has implications on general pharmacokinetic/pharmacodynamic theory, whereby efficacy is linked to only one of the three PDIs in deterministic models. The potency changed 8.9-fold from the first to the fourth weeks. The non-protein-bound AUC/MIC associated with maximal kill at the end of therapy was 50.53 (protein binding = 99.5%). This thioridazine exposure was calculated to extinguish all three M. tuberculosis metabolic populations in human lungs in only 42.9 days of monotherapy. However, this concentration exceeds the 2- to 8-mg/liter thioridazine concentration in serum known to be lethal to humans. Therefore, the way forward for phenothiazine monotherapy that also reduces therapy duration is via synthesis of less toxic congeners.

Thioridazine lacks bactericidal activity in an animal model of extracellular tuberculosis.

OBJECTIVES: The antipsychotic drug thioridazine is active in the murine model of tuberculosis infection, which is predominantly intracellular in nature. Recent clinical reports suggest that thioridazine may play a role in the treatment of drug-resistant tuberculosis. We studied the tuberculocidal activity of thioridazine in guinea pigs, which develop necrotic lung granulomas histologically resembling their human counterparts. METHODS: Pharmacokinetic studies were performed in guinea pigs to establish human-equivalent doses of thioridazine. Guinea pigs were aerosol-infected with ∼100 bacilli of Mycobacterium tuberculosis and single-drug treatment was started 4 weeks later with a range of thioridazine doses daily (5 days/week) for up to 4 weeks. Control animals received no treatment or 60 mg/kg isoniazid. RESULTS: The human-equivalent dose of thioridazine was determined to be 5 mg/kg with saturable absorption noted above 50 mg/kg. At the start of treatment, the lung bacterial burden was ∼6.2 log10 cfu. Although isoniazid reduced bacillary counts more than 10-fold, thioridazine monotherapy showed limited killing over the range of doses tested, reducing lung bacillary counts by 0.3-0.5 log10 following 1 month of treatment. Thioridazine was tolerated up to 40 mg/kg. CONCLUSIONS: Thioridazine has limited bactericidal activity against extracellular bacilli within necrotic granulomas. Its contribution to the sterilizing activity of combination regimens against drug-susceptible and drug-resistant tuberculosis remains to be determined.

Potential therapy of multidrug-resistant and extremely drug-resistant tuberculosis with thioridazine.

Multidrug-resistant tuberculosis (MDRTB) infections that continue to increase in frequency globally have progressed to become extremely drug-resistant tuberculosis (XDRTB). The therapeutic problems associated with MDRTB pale in comparison to those for XDRTB where mortality is high. This mini-review highlights the evidence that supports the use of the phenothiazine neuroleptic thioridazine for the therapy of XDRTB. Although thioridazine does produce some serious side-effects, the poor prognosis associated with an XDRTB infection of a patient that presents with AIDS merits that the use of thioridazine for therapy of XDRTB is seriously considered. A recommended protocol is presented.

Thioridazine: the good and the bad.

Thioridazine is a phenothiazine drug which has previously been extensively used for its antipsychotic properties as it is associated with a low risk of extra-pyramidal side-effects. There is good evidence to suggest that, in common with other phenothiazine drugs, thioridazine has important anti-microbial activity and is a potential candidate for development as an anti-microbial drug against multi-resistant organisms, including drug-resistant strains of M. tuberculosis. The clinical pharmacology and toxicity profile of thioridazine are reviewed in this article and the implications for future drug development along with the patent are discussed.

Metabolic activation of the phenothiazine antipsychotics chlorpromazine and thioridazine to electrophilic iminoquinone species in human liver microsomes and recombinant P450s.

The phenothiazine-derived antipsychotics, namely chlorpromazine and thioridazine, have been associated with very rare but severe incidences of hepatotoxicity in patients. While the mechanism of idiosyncratic hepatotoxicity remains unknown, it is possible that metabolic activation and subsequent covalently binding of reactive metabolites to cellular proteins play a causative role. Studies were initiated to determine whether chlorpromazine and thioridazine undergo cytochrome P450 (P450)-mediated bioactivation in human liver microsomes to electrophilic intermediates. LC/MS/MS analysis of incubations containing chlorpromazine or thioridazine in the presence of NADPH and glutathione (GSH) revealed the formation of GSH conjugates derived from the addition of the sulfydryl nucleophile to monohydroxy metabolites of chlorpromazine and thioridazine, respectively. Formation of reactive intermediates of chlorpromazine and thioridazine was primarily mediated by heterologously expressed recombinant CYP2D6, and to a less extent, CYP1A2. The 7-hydroxyl metabolites of chlorpromazine and thioridazine were also detected by tandem mass spectrometry. A tentative pathway states that after initial 7-hydroxylation, a bioactivation sequence involves P450-catalyzed oxidation of the phenothiazine core to an electrophilic quinone imine intermediate, which is subsequently attacked by glutathione yielding the sulfydryl conjugates. The results from the current investigation constitute the first report on the cytochrome P450-catalyzed bioactivation of the phenothiazine antipsychotics chlorpromazine and thioridazine.

Comparative metabolic capabilities and inhibitory profiles of CYP2D6.1, CYP2D6.10, and CYP2D6.17.

Polymorphisms in the cytochrome P450 2D6 (CYP2D6) gene are a major cause of pharmacokinetic variability in human. Although the poor metabolizer phenotype is known to be caused by two null alleles leading to absence of functional CYP2D6 protein, the large variability among individuals with functional alleles remains mostly unexplained. Thus, the goal of this study was to examine the intrinsic enzymatic differences that exist among the several active CYP2D6 allelic variants. The relative catalytic activities (enzyme kinetics) of three functionally active human CYP2D6 allelic variants, CYP2D6.1, CYP2D6.10, and CYP2D6.17, were systematically investigated for their ability to metabolize a structurally diverse set of clinically important CYP2D6-metabolized drugs [atomoxetine, bufuralol, codeine, debrisoquine, dextromethorphan, (S)-fluoxetine, nortriptyline, and tramadol] and the effects of various CYP2D6-inhibitors [cocaine, (S)-fluoxetine, (S)-norfluoxetine, imipramine, quinidine, and thioridazine] on these three variants. The most significant difference observed was a consistent but substrate-dependent decease in the catalytic efficiencies of cDNA-expressed CYP2D6.10 and CYP2D6.17 compared with CYP2D6.1, yielding 1.32 to 27.9 and 7.33 to 80.4% of the efficiency of CYP2D6.1, respectively. The most important finding from this study is that there are mixed effects on the functionally reduced allelic variants in enzyme-substrate affinity or enzyme-inhibitor affinity, which is lower, higher, or comparable to that for CYP2D6.1. Considering the rather high frequencies of CYP2D6*10 and CYP2D6*17 alleles for Asians and African Americans, respectively, these data provide further insight into ethnic differences in CYP2D6-mediated drug metabolism. However, as with all in vitro to in vivo extrapolations, caution should be applied to the clinical consequences.

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.

Factors affecting drug concentrations and QT interval during thioridazine therapy.

The objective of this study was to investigate factors affecting steady-state plasma concentrations of thioridazine. A cross-sectional study of patients receiving chronic thioridazine was employed. Common allelic variants of CYP2D6 and CYP2C19, as well as thioridazine and metabolite concentrations and QTc intervals, were determined. In 97 patients, dose-corrected plasma concentrations (C/Ds) of thioridazine and metabolites were correlated with age but not sex or CYP2C19 genotype. Patients with no functional CYP2D6 alleles (n=9) had significantly higher C/D for thioridazine (P=0.017) and the ring sulfoxide metabolite and a significantly higher thioridazine/mesoridazine ratio compared with those with >/=1 functional CYP2D6 allele (n=82). Smokers had significantly lower C/D for thioridazine, mesoridazine, and sulforidazine and significantly lower thioridazine/ring sulfoxide ratios than non-smokers. QTc interval was not significantly affected by CYP2D6 or CYP2C19 genotypes. Plasma concentrations of thioridazine are influenced by age, smoking, and CYP2D6 genotype, but CYP2D6 genotype does not appear to influence on-treatment QTc interval.

Postmortem redistribution of two antipsychotic drugs, haloperidol and thioridazine, in the rat.

Antipsychotic drugs may be associated with arrhythmia, ventricular fibrillation, or torsades de pointes, which can result in sudden death. These drugs could therefore be found in postmortem toxicological analyses of autopsy specimens following unexplained sudden death. The drug concentrations in tissues and body fluids change between the death and postmortem specimens collection because of postmortem redistribution. For this reason, it is often difficult to interpret the postmortem analysis. The aim of this study was to investigate postmortem redistribution of the two cardiotoxic antipsychotic drugs, haloperidol and thioridazine, in order to interpret the postmortem analysis. We have chosen the rat as an animal model. The rats received 1 mg/kg of haloperidol and 5 mg/kg of thioridazine by intraperitoneal injection. They were sacrificed and left at room temperature for 2, 6, 12, 24, or 48 h, at which times blood and tissue samples were taken. The drug analyses in tissues and blood were done using a liquid chromatography- tandem mass spectrometry method. Our results show that there is a redistribution of the two drugs from the lung to the cardiac blood. The concentration of the antipsychotic drugs in the lung decreased rapidly, whereas in the cardiac blood, this concentration increased within the first 2 h postmortem. By 48 h after death, the concentrations of the antipsychotic drugs were about twice as high as the initial concentrations in the cardiac blood. For the lungs, a decrease of 50% was observed between 0 and 48 h. Only myocardium and muscle concentrations did not change with the postmortem delay.

Prediction of drug-drug interactions for AUCoral of high clearance drug from in vitro data: utilization of a microtiter plate assay and a dispersion model.

The purpose of this study was to propose a new method to predict in vivo drug-drug interactions (DDIs) for a high clearance drug from in vitro data. As the high clearance drug, NE-100 (N, N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]ethylamine monohydrochloride) was used. First, approach based on I(u)/K(i) value was used for the prediction of DDIs between NE-100 and concomitant drugs. When the K(i) values (K(i-cal)) obtained from the microtiter plate (MTP) assay and the reported K(i) values (K(i-rep)) for these drugs were used to predict increases at levels of NE-100 AUC(oral) (AUC(oral) ratio), the AUC(oral) ratios from the I(u)/K(i-cal) correlated with those from the I(u)/K(i-rep). This result suggests that the K(i-cal) from the MTP assay can be used for prediction of DDIs instead of the K(i-rep) value. Second, a new approach combining the inhibition rate (R) calculated from the MTP assay and two physiological models was used to predict DDIs. When the AUC(oral) ratios of NE-100 by various drugs were predicted using the R value and the well-stirred model, the ratios were similar to those predicted using the I(u)/K(i). However, after co-administration of drugs such as quinidine, propafenone and thioridazine (potent inhibitors of CYP2D6), the NE-100 AUC(oral) ratios predicted from the dispersion model was much greater than those from well-stirred model. This result shows that application of the dispersion model to the prediction method using the R value might sensitively and precisely predict the increased levels of AUC(oral) by DDIs for high clearance drug, compared with the prediction method using I(u)/K(i) value.

Characterization of human cytochrome p450 enzymes involved in the metabolism of the piperidine-type phenothiazine neuroleptic thioridazine.

The aim of the present study was to identify human cytochrome P450 enzymes (P450s) involved in mono-2-, di-2-, and 5-sulfoxidation, and N-demethylation of the piperidine-type phenothiazine neuroleptic thioridazine in the human liver. The experiments were performed in vitro using cDNA-expressed human P450s (Supersomes 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, and 3A4), liver microsomes from different donors, and P450-selective inhibitors. The results indicate that CYP1A2 and CYP3A4 are the main enzymes responsible for 5-sulfoxidation and N-demethylation (34-52%), whereas CYP2D6 is the basic enzyme that catalyzes mono-2- and di-2-sulfoxidation of thioridazine in human liver (49 and 64%, respectively). Besides CYP2D6, CYP3A4 contributes to a noticeable degree to thioridazine mono-2-sulfoxidation (22%). Therefore, the sulforidazine/mesoridazine ratio may be an additional and more specific marker than the mesoridazine/thioridazine ratio for assessing the activity of CYP2D6. In contrast to promazine and perazine, CYP2C19 insignificantly contributes to the N-demethylation of thioridazine. Considering serious side-effects of thioridazine and its 5-sulfoxide (cardiotoxicity), as well as strong dopaminergic D2 and noradrenergic alpha1 receptor-blocking properties of mono-2- and di-2-sulfoxides, the obtained results are of pharmacological and clinical importance, in particular, in a combined therapy. Knowledge of the catalysis of thioridazine metabolism helps to choose optimum conditions (a proper coadministered drug and dosage) to avoid undesirable drug interactions.

Practical application of guinea pig telemetry system for QT evaluation.

The purpose of this study was to evaluate a telemetry system for examining QT evaluation in the conscious free-moving guinea pig using 10 reference compounds whose effects on human QT interval are well established: 8 positive references (bepridil, terfenadine, cisapride, haloperidol, pimozide, quinidine, E-4031 and thioridazine), and 2 negative references (propranolol and nifedipine). Pharmacokinetic experiments were also performed for the 8 positive references. Telemetry transmitters were implanted subcutaneously in male Hartley guinea pigs, and the RR and QT intervals were measured. All 8 positive references prolonged QTc (QTc = k x QT/RR(1/2)) 10% or more during the 60 min observation period. When the values of the QTc changes were plotted against the serum concentrations, the resulting curves exhibited an anticlockwise hysteresis loop for all 8 references. In guinea pigs treated with haloperidol, changes of the T-wave shape from positive to flat were observed. The 2 negative references did not prolong the QTc. These findings suggest that the present telemetry guinea pig model is useful for QT evaluation in the early stages of drug development, because of the small body size of guinea pigs and their action potential configuration, which is similar to that of humans.

Repeated dosing with donepezil does not affect the safety, tolerability or pharmacokinetics of single-dose thioridazine in young volunteers.

AIM: To investigate the effects of donepezil at steady state on the safety, tolerability and pharmacokinetics of a single dose of thioridazine, in healthy subjects. METHODS: An open, two-way, balanced crossover study, in 12 subjects (six men and six women) aged 19-41 years. During both treatment periods, subjects received a single oral dose of 50 mg thioridazine; in one period the thioridazine was given alone, and in the other period it was given together with the last of 15 daily, oral doses of donepezil 5 mg. The 'washout' periods were 1 week when thioridazine was given first, and 2 weeks when thioridazine was given last. Plasma concentrations of thioridazine were measured after each dose, and pharmacokinetic parameters were determined. Interactions were tested by using an equivalence analysis in which thioridazine was the 'Reference' and thioridazine + donepezil the 'Test' regimen. Safety and tolerability were monitored. RESULTS: Donepezil had no marked effect on the pharmacokinetics of thioridazine, as judged by the equivalence analysis of AUC(0-tn), AUC(0-infinity), t((1/2)) and t(max). C(max) was very similar in the 'Test' and 'Reference' regimens, but the confidence intervals were too wide to confirm equivalence. Donepezil was well tolerated, whereas thioridazine was associated with light-headedness, tiredness and postural hypotension, irrespective of whether or not donepezil was given concurrently. CONCLUSIONS: Repeated dosing with donepezil, 5 mg daily for 2 weeks, had no significant effect on the safety, tolerability or pharmacokinetics of thioridazine. Thioridazine was poorly tolerated.

QTc interval lengthening is related to CYP2D6 hydroxylation capacity and plasma concentration of thioridazine in patients.

Thioridazine cardiotoxicity has been associated with a prolonged heart-rate corrected QT (QTc) interval. However, no systematic studies have been performed on patients at therapeutic doses. The present study aimed to evaluate the influence of dose and plasma concentration of thioridazine and CYP2D6 enzyme status on the QTc interval in psychiatric patients. Sixty-five Spanish European psychiatric patients receiving thioridazine antipsychotic monotherapy were studied. The plasma levels of thioridazine and its metabolites were determined by high-performance liquid chromatography. All patients were phenotyped for CYP2D6 activity with debrisoquine during treatment. Thirty-five patients (54%) had a QTc interval over 420 ms. The lengthening of QTc interval was correlated with plasma concentration (p < 0.05) and daily dose (p < 0.05) of thioridazine. CYP2D6 enzyme hydroxylation capacity, evaluated by debrisoquine metabolic ratio (MR) (p < 0.05) and thioridazine/mesoridazine ratio (p < 0.05), was also correlated with QTc intervals. The present study shows the relationship between QTc interval lengthening among psychiatric patients treated at therapeutical doses with the dose and the plasma concentration of thioridazine. Since debrisoquine MR has been shown to be correlated with the QTc intervals, CYP2D6 enzyme hydroxylation capacity might be relevant in determining the risk for QTc interval lengthening. Patients with impaired CYP2D6 enzyme activity due to enzyme inhibition by thioridazine might be more prone to increased risk of sudden death due to torsade de pointes type cardiac dysrhythmia.

Enantiomers' potential in psychopharmacology--a critical analysis with special emphasis on the antidepressant escitalopram.

Stereochemistry is now influencing most areas of pharmacotherapy, with a growing awareness in the field of psychiatry and, more specifically, depression. This is due to the fact that the enantiomers of many chiral drugs may have distinct pharmacological, pharmacokinetic and/or pharmacogenetic profiles. Consequently, in some instances there may be an advantage in using a single enantiomer over the racemic form-thus providing a basis for the development of new therapeutic agents, as well as the potential to improve current treatments. This review highlights some of the potential advantages and disadvantages that using single enantiomers might offer. The principles are exemplified through reference to the stereoselective properties of several established chiral psychotropic drugs, including thioridazine, methadone, trimipramine, mianserin, mirtazapine, fluoxetine and citalopram. Emphasis is given to the treatment of depression and how the potential of one pure enantiomer-escitalopram, the S-enantiomer of the selective serotonin reuptake inhibitor citalopram-appears to be fulfilling its preclinical promise in the clinic.

Intracellular distribution of psychotropic drugs in the grey and white matter of the brain: the role of lysosomal trapping.

1. Since the brain is not a homogenous organ (i.e. the phospholipid pattern and density of lysosomes may vary in its different regions), in the present study we examined the uptake of psychotropic drugs by vertically cut slices of whole brain, grey (cerebral cortex) and white (corpus callosum, internal capsule) matter of the brain and by neuronal and astroglial cell cultures. 2. Moreover, we assessed the contribution of lysosomal trapping to total drug uptake (total uptake=lysosomal trapping+phospholipid binding) by tissue slices or cells conducting experiments in the presence and absence of 'lysosomal inhibitors', i.e., the lysosomotropic compound ammonium chloride (20 mM) or the Na(+)/H(+)-ionophore monensin (10 microM), which elevated the internal pH of lysosomes. The initial concentration of psychotropic drug in the incubation medium was 5 microM. 3. Both total uptake and lysosomal trapping of the antidepressants investigated (imipramine, amitriptyline, fluoxetine, sertraline) and neuroleptics (promazine, perazine, thioridazine) were higher in the grey matter and neurones than in the white matter and astrocytes, respectively. Lysosomal trapping of the psychotropics occurred mainly in neurones where thioridazine sertraline and perazine showed the highest degree of lysosomotropism. 4. Distribution interactions between antidepressants and neuroleptics took place in neurones via mutual inhibition of lysosomal trapping of drugs. 5. A differential number of neuronal and glial cells in the brain may mask the lysosomal trapping and the distribution interactions of less potent lysosomotropic drugs in vertically cut brain slices. 6. A reduction (via a distribution interaction) in the concentration of psychotropics in lysosomes (depot), which leads to an increase in their level in membranes and tissue fluids, may intensify the pharmacological action of the combined drugs.

Pharmacokinetics and metabolism of thioridazine during co-administration of tricyclic antidepressants.

1. Because of serious side-effects of thioridazine and tricyclic antidepressants (cardiotoxicity), a possible influence of imipramine and amitriptyline on the pharmacokinetics and metabolism of thioridazine was investigated in a steady state (2-week treatment) in rats. 2. Imipramine and amitriptyline (5 and 10 mg kg(-1) i.p., respectively) elevated 30 and 20 fold, respectively, the concentration of thioridazine (10 mg kg(-1) i.p.) and its metabolites (N-desmethylthioridazine, 2-sulphoxide, 2-sulphone, 5-sulphoxide) in blood plasma. Similar, yet weaker increases in the thioridazine concentration were found in the brain. Moreover, an elevation of thioridazine/metabolite ratios was observed. 3. Imipramine and amitriptyline added to control liver microsomes in vitro inhibited the metabolism of thioridazine via N-demethylation (an increase in K(m)), mono-2-sulphoxidation (an increase in K(m) and a decrease in V(max)) and 5-sulphoxidation (mainly a decrease in V(max)). Amitriptyline was a more potent inhibitor than imipramine of the thioridazine metabolism. 4. The varying concentration ratios of antidepressant/thioridazine in vivo appear to be more important to the final result of the pharmacokinetic interactions than are relative direct inhibitory effects of the antidepressants on thioridazine metabolism observed in vitro. 5. Besides direct inhibition of the thioridazine metabolism, the decreased activity of cytochrome P-450 towards 5-sulphoxidation, produced by chronic joint administration of thioridazine and the antidepressants, seems to be relevant to the observed in vivo interaction. 6. The obtained results may also point to inhibition of another, not yet investigated, metabolic pathway of thioridazine, which may be inferred from the simultaneous elevation of concentrations of both thioridazine and the measured metabolites.

Psychomotor effects of zaleplon and thioridazine coadministration.

OBJECTIVE: To assess the potential pharmacokinetic and pharmacodynamic interaction of zaleplon and thioridazine administered concomitantly in healthy volunteers. METHODS: A three-period, double-blind, randomized crossover study of the psychomotor effects of single oral doses of zaleplon 20 mg alone, thioridazine 50 mg alone, or the two drugs administered concomitantly was performed in 12 healthy subjects. Pharmacodynamic testing was performed before, and at 1, 2, 4, and 8 h after drug administration. Critical flicker fusion (CFF), tapping rate (TR), reaction time (RT) with dominant and nondominant hands, and digit symbol substitution test (DSST) were used to assess psychomotor performance. RESULTS: Pharmacokinetic results showed that coadministration of zaleplon and thioridazine did not alter the pharmacokinetic profile of either drug. In both CFF and TR tests, values for change from baseline with combined treatment were not significantly different from those with thioridazine at any time point, indicating no pharmacodynamic interaction. RT test values with coadministered treatment were significantly different from those with thioridazine alone at 1 h after administration, indicating additivity. Supra-additivity was observed in DSST results at 1, 2, and 4 h. There was no interaction at 8 h. CONCLUSION: The results of single-dose administration showed an additive pharmacodynamic interaction between zaleplon and thioridazine at 1 h in one of four tests and supra-additivity for 4 h in another test. This interaction is relatively short in duration due to the short half-life of zaleplon.