Haloperidol In Plasma Research Articles

High-Performance Liquid Chromatographic Assay for the Determination of Haloperidol in Plasma

Abstract A sensitive, reproducible and accurate high performance liquid chromatographic (HPLC) method for the quantitative determination of haloperidol in plasma has been developed and validated. Sample preparation involves extraction of haloperidol and diazepam (internal standard) from 0.5 mL plasma. The separation was carried out in a stainless steel, resolve C18 column with a mobile phase composed of a mixture of 55% methanol and 45% HPLC water containing 0.2 M ammonium acetate and adjusted to an apparent pH 7.2. The mobile phase was pumped at a flow rate of 1.5 mL/min. The column oven temperature was adjusted at 38°C and the effluent was monitored at 249 nm. The retention times for the internal standard and haloperidol were found to be 5.1 and 6.3 minutes, respectively. Peak-height ratios of the drug to the internal standard were used for the quantification of haloperidol in the plasma samples. The average (±SD) absolute and relative recovery of haloperidol were 97±3.6% and 100 6±1.52%, respectively. ...

Neurotoxic implications of haloperidol metabolism

A sensitive and selective method for the determination of the pyridinium metabolite (HPP+) derived from the antipsychotic drug haloperidol (HP) in brain tissue, plasma and urine using high-performance liquid chromatography with fluorescence detection is described. The HPP+ present in biological samples was extracted using a Sep-Pak C18 cartridge. Recoveries of HPP+ ranged from 78 to 90%. Final separation and quantitative estimations of HPP+ were achieved on a C18 reversed-phase column employing a mobile phase of acetonitrile—30 mM ammonium acetate (40:60, v/v) containing 10 mM triethylamine and adjusted to pH 3 with trifluoroacetic acid. The fluorescence detection utilized an excitation wavelength of 304 nm and an emission wavelength of 374 nm. Standard curves were linear in the range of 2.5–100 ng/ml for brain tissue homogenate and plasma samples and 10–500 ng/ml for urine samples. The detection limit of HPP+ was about 1 ng/ml in all biological samples. The concentrations of HPP+ in brain tissue, plasma and urine from HP-treated rats were determined using this method.

Simultaneous determination of plasma haloperidol and its metabolite reduced haloperidol by liquid chromatography with electrochemical detection Plasma levels in schizophrenic patients treated with oral or intramuscular depot haloperidol

A simple and highly sensitive liquid chromatographic method with electrochemical detection for the simultaneous determination of haloperidol and its metabolite reduced haloperidol in human plasma has been developed. The sample preparation for the analysis involves a simple one-step extraction procedure with 10% methylene chloride in pentane. The compounds were separated on a cyano column maintained at a temperature of 40°C and were detected electrochemically by a flow-through analytical cell kept at +0.95 V. The standard curve is linear over the range of 0.1 to 15 ng/ml and the lower limit of quantitation is 0.1 ng/ml for haloperidol and 0.25 ng/ml for reduced haloperidol which is equivalent to approximately 40 pg on column when 1 ml of plasma was used for the analysis. The lower limit of quantitation for reduced haloperidol can be extended to 0.1 ng/ml if 2 ml of plasma is used in the analysis. The coefficient of variation of the determination of plasma levels by this method over the standard curve concentration range was less than 10%. Commonly co-administered drugs and other neuroleptics used in conjunction with haloperidol did not interfere in the determination of either haloperidol or reduced haloperidol. This method has been successfully used for the determination of haloperidol and reduced haloperidol in plasma and their levels in patients treated with various doses oral haloperidol or intramuscular haloperidol decanoate are reported.

Steady-State Pharmacokinetics of Haloperidol and Reduced Haloperidol in Schizophrenic Patients: Analysis of Factors Determining their Concentrations in Hair

Profiles of the steady‐state concentrations of haloperidol (HL) and its major metabolite, reduced haloperidol (RHL), in plasma versus time were determined in 10 Japanese patients whose schizophrenic symptoms were clinically controlled by fixed, oral maintenance doses (4–30 mg/day, three times a day) for >4 months. These data were used to determine the pharmacokinetic factor(s) that correlate best with HL and RHL concentrations in hair. The concentrations of HL and RHL in plasma or hair were simultaneously measured by high‐performance liquid chromatography with an electrochemical detector. The observed values of minimal and maximal concentrations in plasma (Cmin and Cmax' respectively) varied widely among patients: 3.0–22.9 and 6.2–32.7 ng/mL for HL and 2.8–21.4 and 5.7–33.3 ng/ml for RHL, respectively. The ratio of the area under the plasma concentration‐time curve (AUC) of RHL for 1 day to that of HL also ranged widely from 0.39 to 1.99 (1.04 ± 0.48, mean ± standard deviation). When the concentration of HL or RHL in hair was compared with the daily dose of HL and respective AUC, Cmax' or trough concentration in the plasma in the morning, the parameter that best correlated with the concentration of HL in hair was AUC. The concentration of RHL in hair correlated with all three parameters, but the correlation with AUC was better than that with Cmax. Therefore, the concentrations of these substances in hair were considered to be representative of their mean amounts in the body.

Determination of the pyridinium metabolite derived from haloperidol in brain tissue, plasma and urine by high-performance liquid chromatography with fluorescence detection

A sensitive and selective method for the determination of the pyridinium metabolite (HPP +) derived from the antipsychotic drug haloperidol (HP) in brain tissue, plasma and urine using high-performance liquid chromatography with fluorescence detection is described. The HPP + present in biological samples was extracted using a Sep-Pak C 18 cartridge. Recoveries of HPP + ranged from 78 to 90%. Final separation and quantitative estimations of HPP + were achieved on a C 18 reversed-phase column employing a mobile phase of acetonitrile—30 m M ammonium acetate (40:60, v/v) containing 10 m M triethylamine and adjusted to pH 3 with trifluoroacetic acid. The fluorescence detection utilized an excitation wavelength of 304 nm and an emission wavelength of 374 nm. Standard curves were linear in the range of 2.5–100 ng/ml for brain tissue homogenate and plasma samples and 10–500 ng/ml for urine samples. The detection limit of HPP + was about 1 ng/ml in all biological samples. The concentrations of HPP + in brain tissue, plasma and urine from HP-treated rats were determined using this method.

Regional distribution and kinetics of haloperidol binding in human brain: A pet study with [18F]haloperidol

The regional distribution and the kinetics of haloperidol uptake in human brain were examined using [18F]haloperidol and PET in 9 controls and 5 schizophrenics while on haloperidol medication and after haloperidol washout. The regional distribution of [18F]N-methylspiroperidol, a tracer for D2 receptors, was measured in 1 normal subject for comparison. The uptake of [18F]haloperidol in the whole brain in normals was high (6.6% of the injected dose at 2 hr), and regional distribution was much more extensive than could be accounted for by the distribution of dopamine D2 receptors. In normals, the cerebellum, basal ganglia, and thalamus showed a greater concentration than the cortex, and there was minimal clearance of 18F from the brain during the 10-hr period of the study. Medicated schizophrenics showed a total brain uptake of 4.0% and had a significant clearance of [18F]haloperidol from brain and a higher concentration of [18F]haloperidol in plasma. After withdrawal from medication, [18F]haloperidol clearance from brain became slower than while on medication. These results are discussed in terms of the pharmacokinetics of haloperidol in the human brain and its binding to dopamine D2 receptors and to sigma receptors.

Level of haloperidol in plasma is related to electroencephalographic findings in patients who improve

This study analyzed interrelationships among plasma level of haloperidol (HAL), electroencephalographic (EEG) changes, and clinical response in 37 acutely exacerbated schizophrenic patients after a 6-week period of treatment. Two hypotheses were tested: (1) EEG theta response to HAL depends on levels of HAL in plasma, and this relationship is expressed in patients showing a clear clinical response (responders). (2) Responders and nonresponders are characterized by a different neuroleptic EEG profile. EEG examinations (resting, waking EEG) were performed at study entry, end point of the placebo period (“baseline”), and weekly during the entire HAL treatment period. EEG response was measured by power spectral changes in four frequency bands (delta, theta, alpha, and beta); clinical response was assessed by the Brief Psychiatric Rating Scale. There was a significant relationship between HAL plasma levels and EEG theta activity for treatment responders, whereas no relationship was detected for the nonresponders. Furthermore, there were EEG changes (in the delta and alpha bands) that depended on clinical response but did not show any relationship, either in responders or nonresponders, to HAL plasma levels. These results supported both hypotheses.

Simultaneous determination of haloperidol and its metabolite, reduced haloperidol, in plasma, blood, urine and tissue homogenates by high-performance liquid chromatography

A high-performance liquid chromatographic method was developed for the simultaneous determination of haloperidol and reduced haloperidol in human plasma, urine and rat tissue homogenates using bromperidol as an internal standard. The method involved extraction followed by injection of 50–80 μl of the aqueous layer onto a C 18 reversed-phase column. The mobile phase was 0.5 M phosphate buffer—acetonitrile—methanol (58:31:11, v/v/v) and the flow-rate was 0.6 ml/min. The column effluent was monitored by ultraviolet detection at 214 nm. The retention times for reduced haloperidol, haloperidol and bromperidol were 5.4, 7.2 and 8.4 min, respectively. The detection limits for haloperidol and reduced haloperidol in human plasma were both 0.5 ng/ml, and the corresponding values in human urine were both 5 ng/ml. The coefficients of variation of the assay were generally low (below 10.7%) for plasma, urine, blood and tissue homogenates. No interferences from endogenous substances or any drug tested were found.

Haloperidol and reduced-haloperidol concentrations in plasma from chronic schizophrenic patients

Haloperidol and reduced-haloperidol concentrations in plasma from chronic schizophrenic patients

High-performance liquid chromatographic procedure for the determination of clozapine, haloperidol, droperidol and several benzodiazepines in plasma

High-performance liquid chromatographic procedure for the determination of clozapine, haloperidol, droperidol and several benzodiazepines in plasma

High-performance liquid chromatographic analysis of haloperidol and hydroxyhaloperidol in plasma after solid-phase extraction

High-performance liquid chromatographic analysis of haloperidol and hydroxyhaloperidol in plasma after solid-phase extraction

An improved sensitive assay for simultaneous determination of plasma haloperidol and reduced haloperidol levels by liquid chromatography using a coulometric detector.

A simple, highly sensitive and specific high-performance liquid chromatographic method that uses a coulometric detector for the simultaneous assay of haloperidol and reduced haloperidol in human plasma has been developed, using bromoperidol as the internal standard. A reversed phase C8 5-microns column (25 x 0.46 cm) and a mobile phase of phosphate buffer (pH 7.0), acetonitrile, and methanol (40:20:40 vol/vol) are used for separating the analytes. The analytes are extracted from alkalinized plasma using a mixture of pentane and isopropanol (95:5 vol/vol) and purified by back extraction into a perchloric acid solution. Teflon tubes with screw caps are used throughout the extraction work. The compounds are oxidized at a potential of +0.90 V against a Ag/AgCl reference electrode. The detection limit of the assay is 50 ng/L using 1 mL of plasma. The average interassay coefficient of variation for samples of concentration 1-40 micrograms/L is approximately 8%. Possible drug interferences in the assay have been studied. The absolute recovery of the method is approximately 80%. The assay has been validated by quantitating 150 schizophrenic patients' samples.

Haloperidol and Reduced Haloperidol Concentrations in Plasma and Red Blood Cells from Chronic Schizophrenic Patients

In a double-blind, placebo-controlled study, 15 drug-free chronic schizophrenic inpatients were treated with a fixed dose of haloperidol for 6 weeks. Haloperidol and its metabolite, reduced haloperidol, were measured in plasma and red blood cells after 2, 4, and 6 weeks of treatment. Behavioral change was rated using the Brief Psychiatric Rating Scale (BPRS). Not only the raw concentrations, but also blood compartment sums and ratios of these four drug measurements were tested for their strength of association with behavioral improvement. Positive associations with some BPRS subscales at some time points emerged; however, no significant correlations were found to extend across all time points measured. There was a trend in this cohort for negative symptom improvement to be associated with the ratio of haloperidol to reduced haloperidol in red blood cells. The ratio of haloperidol to reduced haloperidol in plasma was always greater than that in the red blood cells for all patients, reflecting an accumulation of the metabolite in red blood cells.

An ultrasensitive method for the measurement of haloperidol and reduced haloperidol in plasma by high-performance liquid chromatography with coulometric detection.

A new analytical method has been developed for the simultaneous quantitation of haloperidol and reduced haloperidol in plasma. The method is based on high performance liquid chromatography (HPLC) with coulometric detection. The extraction and sample clean up procedures are simple and rapid to execute, yet yield chromatograms virtually free of interference from endogenous plasma constituents, such that the extraordinary sensitivity of the coulometric detector can be exploited fully. The detection limits for haloperidol and reduced haloperidol are 20 pg/ml plasma, and the limits of quantitation are 50 pg/ml for both drug and metabolite. Standard curves were linear down to 50 pg/ml with coefficients of variation of less than 7.0% at the limits of quantitation. The method was applied to the study of the plasma levels of haloperidol and reduced haloperidol in two healthy subjects. It was possible to monitor the plasma levels of haloperidol for at least 96 h (4 days) after the administration of a 5-mg oral dose of haloperidol. It was also possible to monitor reduced haloperidol levels over 96 h in one subject, although the metabolite was not detectable in the plasma of the other at any stage.

Sensitive Electrochemical High-Performance Liquid Chromatography Assay for the Simultaneous Determination of Haloperidol and Reduced Haloperidol

An electrochemical HPLC method for the simultaneous determination of haloperidol and reduced haloperidol in plasma is presented. Chlorohaloperidol serves as the internal standard. A cyanopropyl bond elut column was used for sample preparation. The eluate was evaporated and reconstituted with mobile phase and injected onto a nitrile bonded column. The chromatographic system consisted of an ESA Coulochem detector operated in the screen mode. Intra- and interassay coefficients of variation for both compounds were <7%, with a sensitivity limit of 20pg on the column. A plasma level–time profile is presented to illustrate the sensitivity and applicability of this assay in small animal and human pharmacokinetic studies.

Reversed-phase ion-pair liquid chromatographic method for the determination of low concentrations of haloperidol in plasma

A sensitive liquid chromatographic method for the determination of haloperidol in plasma is described. The efficient and simple extraction procedure, followed by reversed-phase ion-pair liquid chromatography on a 3-μm octadecylsilica column and UV absorbance detection, makes it possible to determine concentrations down to 0.5 nmol/l with acceptable precision. In a pharmacokinetic study, in which 5 mg of haloperidol were given orally, the plasma levels were followed for 48 h.

A rapid and simplified extraction of haloperidol from plasma or serum with Bond Elut C 18 cartridge for analysis by high performance liquid chromatography

This method for the determination of haloperidol (HAL) in plasma is based on high-performance liquid chromatography (HPLC) with a reversed-phase column, ODS-C 18. HAL is rapidly extracted from human plasma by using Bond Elut C 18 cartridge and its recovery is over 90%. The mobile phase is a mixture of 1% acetate/acetonitrile/tetrahydrofuran/triethylamine (69.5:28.2:1.9:0.4, by vol.). The method is rapid, simple and free from intereferences and gives good precision.

Review of Haloperidol Blood Level and Clinical Response

The studies of relationship between haloperidol plasma levels and clinical response in schizophrenia have yielded variable results. A therapeutic window for haloperidol may exist, but the evidence for it is inconsistent. Future studies of this problem using larger patient samples would permit the investigation of interactions between the clinical predictors and the haloperidol plasma levels in the determination of clinical outcome. Although the reduced haloperidol in plasma as well as the red blood cell levels of haloperidol and reduced haloperidol or ratios of the metabolite to parent compound may also be related to clinical outcome, the evidence for this relationship is very tentative. More research is needed before routine clinical monitoring of haloperidol blood levels can be recommended.

Measurement of haloperidol and reduced haloperidol in human plasma using réversed-phase high-performance liquid chromatography

Measurement of haloperidol and reduced haloperidol in human plasma using réversed-phase high-performance liquid chromatography

Simultaneous microdetermination of biperiden, haloperidol, and trihexyphenidyl in plasma and its application to pharmacokinetic analysis after concomitant intravenous administration of the drugs to rabbits.

A gas chromatographic method, using a moving precolumn sample injector and a nitrogenphosphorus detector, is presented for the simultancous quantitative analysis of biperiden, haloperidol and trihexyphenidyl in plasma. The drugs were extracted from 1 ml of plasma at pH 10.0 with ether, back-extracted into an acidic solution, and reextracted with ether after alkalinization. Diazepam was used as the internal reference standard. Processed standard curves of biperiden, haloperidol, and trihexyphenidyl plasma samples were linear over the concentration range of 1.25-50 ng/ml. Recoveries were found to be constant at various spiked doses, and the coefficients of variation were less than 11% for each drug. Plasma concentration-time courses after simultaneous administration of the three drugs to rabbits were analyzed by model-independent moment analysis. The volumes of distribution at the steady state per body weight of biperiden, haloperidol, and trihexyphenidyl were determined to be 18.5, 16.7, and 17.6 1/kg, respectively. Plasma clearances of the three drugs were 89.7, 61.7, and 79.9 ml/min/kg, respectively.