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

doi:10.1002/jps.2600811010

Journal of Pharmaceutical Sciences

Volume 81, Issue 10, October 1992, Pages 1008-1011

https://doi.org/10.1002/jps.2600811010 Get rights and content

Abstract

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 (C_min and C_max' 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, C_max' 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 C_max. Therefore, the concentrations of these substances in hair were considered to be representative of their mean amounts in the body.

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Cocaine and codeine were the most common drugs used in these investigations [12–16]. However, a poor relationship between dose and hair concentration has also been observed in patients under constant drug treatment [4,17–21]. Most likely explanations for this discrepancy are suggested to be due to substantive individual biovariability and non-compliance as well as systematic influences due to hair color and cosmetic treatment.
Hair analysis has shown great potential in the detection and control of drug use. Whether an assay is of quantitative value roughly corresponding to the amount of drug consumed, is still a matter of debate. The present investigation was aimed at a possible relationship between the cannabinoid concentration in hair and the cumulative dose in regular users of cannabis. Hair samples from the vertex region of the scalp were obtained from 12 male regular users of cannabis, and 10 male subjects with no experience of cannabis served as controls. None of the subjects had his hair permed, bleached or colored. Cannabis users provided information on drug use such as the current cannabis dose per day, the cumulative cannabis dose of the last 3 months, as well as the frequency of cannabis use during the last year. The concentration of delta-9-tetrahydrocannabinol (THC), cannabinol (CBN) and cannabidiol (CBD) in hair was determined using gas chromatography–mass spectrometry. Cannabinoids were present in any hair sample of cannabis users, but were not detectable in control specimens. An increase in the amount of cannabinoids in hair with increasing dose was evident. The concentration of major cannabinoids (sum of THC, CBD and CBN) was significantly correlated to either the reported cumulative cannabis dose during the last 3 months or to the cannabis use during the last 3 months estimated from the daily dose and the frequency per year (r = 0.68 or 0.71, p = 0.023 or 0.014). A significant relationship between THC and the amount of cannabis used could not be established. As a conclusion, the sum of major cannabinoids in hair of regular users may provide a better measure of drug use than THC.
Examination of a long-term clozapine administration by high resolution segmental hair analysis
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Moreover, a comparatively good correlation between dosage and hair concentration was reported [5]. Hair segmentation to elucidate the detailed long-term drug history was primarily focused on therapy control of psychiatric patients, e.g. detection of amitriptyline [6], antidepressants and antipsychotic drugs [2], benzodiazepines [7], chlorpromazine [8], clozapine[4], or haloperidol [9,10], other attempts were devoted to the identification of chloroquine [11], piritramide [12] and selegeline compliance control by identification of its metabolites [13]. The use of hair segmentation to receive detailed kinetic information is restricted by substance concentration in hair and corresponding detection limits.
The long-term administration of clozapine could be verified by fine segmentation and analysis of single hairs of one person to examine the history of a multiple poisoning case.
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Total amounts of clozapine down to 30 fg (on column) and its desmethyl metabolite could be analysed in multiple reaction monitoring mode. According to typical sample amounts of ∼16 μg, relevant hair concentrations higher than 1 pg/mg were detected.
Significant and reproducible concentration profiles along the hair fibres revealed characteristic administration cycles. The administration time course -in particular the time of its termination—could be verified with a precision of a few days. The accuracy and reproducibility of the concentration profile was proven based on multiple investigations of single hairs. An individual hair growth rate of 0.55 mm/day was determined with a relative standard deviation of 8% by comparison of concentration profiles in hairs collected after a time span of 165 days.
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2006, Clinica Chimica Acta
Hair differs from other materials used for toxicological analysis because of its unique ability to serve as a long-term storage of foreign substances with respect to the temporal appearance in blood. Over the last 20 years, hair testing has gained increasing attention and recognition for the retrospective investigation of chronic drug abuse as well as intentional or unintentional poisoning. In this paper, we review the physiological basics of hair growth, mechanisms of substance incorporation, analytical methods, result interpretation and practical applications of hair analysis for drugs and other organic substances. Improved chromatographic–mass spectrometric techniques with increased selectivity and sensitivity and new methods of sample preparation have improved detection limits from the ng/mg range to below pg/mg. These technical advances have substantially enhanced the ability to detect numerous drugs and other poisons in hair. For example, it was possible to detect previous administration of a single very low dose in drug-facilitated crimes. In addition to its potential application in large scale workplace drug testing and driving ability examination, hair analysis is also used for detection of gestational drug exposure, cases of criminal liability of drug addicts, diagnosis of chronic intoxication and in postmortem toxicology. Hair has only limited relevance in therapy compliance control. Fatty acid ethyl esters and ethyl glucuronide in hair have proven to be suitable markers for alcohol abuse. Hair analysis for drugs is, however, not a simple routine procedure and needs substantial guidelines throughout the testing process, i.e., from sample collection to results interpretation.
Measurement of flecainide in hair as an index of drug exposure
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In the present study, the plasma concentration of flecainide was not determined to clarify any correlation between the concentration of flecainide in plasma and that in hair. In the case of haloperidol13 and an antimicrobial quinolone, OPC-17116,14 a good correlation was revealed between the concentration in human hair and the plasma AUC. Further study is needed to determine if flecainide in hair correlates with the plasma concentration of flecainide.
We report a method for measuring the concentration of flecainide in hair. An animal study, in which flecainide (1, 5, and 10 mg/kg/day) was orally administered for 1, 2, and 3 weeks to pigmented rats, showed that flecainide concentration in rat hairs newly regrown after administration significantly correlated with both the daily dose and the dosing period. The part of hair containing flecainide continued to grow upward, retaining the drug within the hair structure that had been formed at the time of drug exposure. Flecainide was also determined in human scalp hairs collected from patients treated with flecainide. The drug content of white hairs was much less than that black hairs collected from the same rats and subjects, suggesting the determinant effect of hair pigment on flecainide accumulation in hair. These findings suggest that the analysis of flecainide in hair may be useful for assessing exposure to drug qualitatively. © 2001 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 90:1891–1896, 2001
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2000, Life Sciences
Psillakis et al. have reported on the concentration of carbamazepine recovered from hair samples collected from patients receiving this anti-seizure medication under medical supervision and determined that their was a high correlation between dose and quantitation of recovered analyte. The analyte was identified by two techniques, FPIA (Abbott TDx) and HPLC and the correlation was high for both procedures. In the literature on hair analysis some have suggested that analyte concentration in hair is critically dependent on hair color. In reporting their data Psillakis et al. reported the hair color of each patient but made no attempt to analyze their results in relation to color. This article performs a secondary analysis of the Psillakis et al. data in order to determine whether there is a hair color effect discernible in the recovery of carbamazepine from hair. Analysis of this data set for both the FPIA and HPLC by one-way analysis of variance fails to identify a color effect at p = .05. Weighting the data for per-patient dosage values fails to discern a color effect. Examination of all possible two-color comparisons also fails to identify a statistically significant effect for any subset of combinations. These data suggest that carbamazepine does not exhibit a color effect when using either FPIA or HPLC assay methods.
Hair analysis for abused and therapeutic drugs
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This review focuses on basic aspects and recent studies of hair analysis for abused and therapeutic drugs and is discussed with 164 references. Firstly, biology of hair and sampling of hair specimens have been commented for the sake of correct interpretation of the results from hair analysis. Then the usual washing methods of hair samples and the extraction methods for drugs in hair have been shown and commented on. Analytical methods for each drug have been discussed by the grouping of three analytical methods, namely immunoassay, HPLC–CE and GC–MS. The outcomes of hair analysis studies have been reviewed by dividing into six groups; morphine and related, cocaine and related, amphetamines, cannabinoids, the other abused drugs and therapeutic drugs. In addition, reports on stability of drugs in the living hair and studies on drug incorporation into hair and dose–hair concentration relationships have been reviewed. Applications of hair analysis to the estimation of drug history, discrimination between OTC drug use and illegal drug use, drug testing for acute poisoning, gestational drug exposure and drug compliance have also been reviewed. Finally, the promising prospects of hair analysis have been described.

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

Abstract

Environ. Health Perspect

Sci. Total Environ

J. Forensic Sci

J. Forensic Sci

Z. Rechtsmed

Eur. J. Clin. Pharmacol

Ther. Drug Monit

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