Serum Haloperidol Research Articles

Human CYP2D6 Is Functional in Brain In Vivo: Evidence from Humanized CYP2D6 Transgenic Mice.

CYP2D metabolizes many drugs that act within the brain, and variable expression of CYP2D in the brain may alter local drug and metabolite levels sufficiently to affect behavioral responses. Transgenic mice that express human CYP2D6 (TG) were compared to wild type mice (WT). Following selective inhibition of human CYP2D6 in TG brain, we demonstrated in vivo that human CYP2D6 in the brain was sufficient to alter a drug-induced behavioral response. After a 4-h pre-treatment with intracerebroventricular (i.c.v.) propranolol, CYP2D activity in vivo and in vitro was reduced in TG brain, whereas CYP2D activity in vivo, but not in vitro, was reduced in WT brain. After a 24-h pre-treatment with i.c.v. propranolol, CYP2D activity in vivo and in vitro was reduced in TG brain, whereas CYP2D activity in vivo and in vitro was not changed in WT brain. These results indicate that i.c.v. propranolol irreversibly inhibited human CYP2D6 in TG brain but not mouse CYP2D in TG and WT brain. Pre-treatments with propranolol did not change liver CYP2D activity in vivo or in vitro. Furthermore, 24-h pre-treatment with i.c.v. propranolol resulted in a significant decrease of the haloperidol-induced catalepsy response in TG, but not in WT, without changing serum haloperidol levels in either mouse line. These studies reveal a new tool to selectively and irreversibly inhibit human CYP2D6 in TG brain and indicate that human CYP2D6 has a functional role within the brain sufficient to impact the central nervous system response from peripherally administered drugs.

Pharmacogenomic response of low dose haloperidol in critically ill adults with delirium

PurposeTo characterize the pharmacogenomic response of low-dose haloperidol for delirium treatment in critically ill adults. Materials and methodsSingle-center, pilot study of a convenience sample of ICU adults with delirium treated with low-dose IV haloperidol. Patients were evaluated for delirium with the ICDSC every 8 h. Serum haloperidol concentrations were collected on ICU days 2–6, CYP2D6 and CYP3A4 genotypes were characterized and patients were categorized as extensive (EM), intermediate (IM) or poor metabolizers (PM). ResultsThe 22 patients (median age 67 [IQR 48,77] years; median APACHE III 81[IQR 54,181]; CYP2D6 [EM = 12, IM = 7, PM = 3], CYP3A [EM = 18, IM = 4]) received a median [IQR] daily haloperidol dose of 3.0 [2.4, 4.5] mg. After adjusting for age, SOFA, and ICU day, neither an association between CYP2D6 (IM p = .67/PM p = .25) or CYP3A4 (IM p = .44) metabolizer status and serum haloperidol concentrations was found. After adjusting for age, SOFA, and ICU day, neither an association between daily haloperidol dose (p = .77) or ICDSC score (p = .13) and serum haloperidol concentrations was found. No patient experienced QTc interval prolongation (≥500 ms). ConclusionsThis pilot study, the first to evaluate the pharmacogenomic response of low-dose haloperidol when used to treat delirium in the ICU, suggests CYP2D6/CYP3A4 metabolizer status does not affect the serum haloperidol concentrations.

Propranolol is a mechanism-based inhibitor of CYP2D and CYP2D6 in humanized CYP2D6-transgenic mice: Effects on activity and drug responses.

Genetics and drug interactions contribute to large interindividual variation in human CYP2D6 activity. Here, we have characterized propranolol inhibition of human and mouse CYP2D using transgenic (TG) mice, which express both mouse CYP2D and human CYP2D6, and wild-type (WT) mice. Our purpose was to develop a method for in vivo manipulation of CYP2D6 enzyme activity which could be used to investigate the role of CYP2D6 in drug-induced behaviours. Dextromethorphan metabolism to dextrorphan was used to measure CYP2D activity and to characterize propranolol inhibition in vitro and in vivo. Effects of propranolol pretreatment (24 hr) on serum levels of the CYP2D6 substrate haloperidol and haloperidol-induced catalepsy were also studied. Dextrorphan formation velocity in vitro was threefold higher in liver microsomes of TG compared to WT mice. Propranolol acted as a mechanism-based inhibitor (MBI), inactivating CYP2D in liver microsomes from TG and WT mice, and humans. Pretreatment (24 hr) of TG and WT mice with 20 mg·kg-1 intraperitoneal propranolol reduced dextrorphan formation in vivo and by liver microsomes in vitro. Serum haloperidol levels and catalepsy were increased. Propranolol was a potent MBI of dextrorphan formation in liver microsomes from TG and WT mice, and humans. The inhibition parameters in TG overlapped with those in WT mice and in humans. Inhibition of CYP2D with propranolol in vivo in TG and WT mice altered drug responses, allowing further investigation of variations in CYP2D6 on drug interactions and drug responses.

Drug development and use in the elderly: search for the right dose and dosing regimen

Across the globe over the last few decades, there has been a remarkable increase in the proportion of the population which is elderly, and this trend is set to continue. Data from 10 countries that accounted for about 55% of the world population of 6079 million in the year 2000 provide an overview of this significant shift in demography. Table 1 summarizes the projections for the next 25 years. Hitherto, increases in life expectancy have been most obvious in the affluent countries; however, improvements in public health and disease control are also leading to increases in life expectancy in the less affluent countries. As a result of relatively larger increases in life expectancy at birth, significant shifts in demography are also expected in countries that are at present economically less affluent. The number of elderly people in the world is therefore expected to continue to increase for some considerable time. Interestingly, the most dramatic increases in the proportion of the population who are elderly are anticipated in countries where total populations are projected to decrease (such as Japan, Germany and Italy). Table 1 Age-related demography in 2000 and projected changes in 10 major countries The 2001 population census of the UK revealed that since the census of 1951, the proportion of elderly population above 65 years and 85 years has increased from 16% and 0.4% respectively to 21% and 1.9%, respectively. These changes in demography will have significant effects on the economics generally as well as on the provisions for healthcare. Cardiovascular and neurological diseases and cancers are the most prevalent in the elderly. These three groups of diseases account for about 54% of the total burden of disease in Europe in terms of disability adjusted life years. Of the total gross Hospital and Community Health Services expenditure of £31.9 billion in the year 2001–2002 in the UK, 13% was expended on people aged 65–74 years, 16% on those aged 75–84 years and 10% for people aged 85 years or more. Furthermore, about 55% of the community prescriptions during 2001 in the UK were dispensed for the elderly. Cardiovascular and psychoactive drugs accounted for more than 40% of these prescriptions. In view of many age-related changes in the pharmacokinetics and pharmacodynamics of a drug, the safe and effective prescribing of medicines in the elderly will continue to present a major challenge. This review provides an overview of the issues relevant to development and clinical use of drugs in the elderly population, with particular reference to determining the right dosage and dose regimen and the regulatory requirements that facilitate this process. It also examines whether, as a result of advancing age per se, the dosing regimens in the elderly and the frail elderly might be different from those in the non-elderly.

Cytochrome P450 II D6 gene polymorphisms and the neuroleptic-induced extrapyramidal symptoms in Japanese schizophrenic patients.

The purpose of this study was to examine whether the neuroleptic-induced extrapyramidal symptoms are associated with the CYP2D6 activity. The CYP2D6 gene polymorphisms (CYP2D6*2, CYP2D6*3, CYP2D6*4, CYP2D6*10, and CYP2D6*12) were genotyped in 196 normal controls and 320 schizophrenic patients receiving neuroleptics. The relationships with susceptibility to extrapyramidal symptoms (EPS) and tardive dyskinesia, and with steady-state serum haloperidol levels in maintenance therapy, were investigated. The allele frequency of CYP2D6*2 was significantly higher, while that of CYP2D6*10 tended to be higher in the schizophrenic patients susceptible to acute EPS. The steady-state serum haloperidol levels per daily dosage were observed to be significantly higher in schizophrenic patients with the mutant-type homozygote of CYP2D6*2, while this difference was trend level in those of CYP2D6*10. However, no significant difference was observed in the distribution of both CYP2D6*2 (C2938T) and CYP2D6*10 (C188T) polymorphisms between schizophrenic patients with or without tardive dyskinesia. The present results suggest that the homozygotes of CYP2D6*2 and CYP2D6*10 appear to be a susceptibility factor for developing acute EPS in schizophrenic patients and for impaired neuroleptic metabolism in Japanese schizophrenic patients.

Interindividual variation of serum haloperidol concentrations in Japanese patients--clinical considerations on steady-state serum level-dose ratios.

Marked interpatient variability in haloperidol (HAL) level-dose (L/D) ratios makes it difficult to use the administered dose for predicting serum concentrations. To investigate the effect of dose, age, total body weight and co-medication on steady-state HAL L/D ratios. Retrospective analysis of dose and HAL blood level data from 168 patients. The HAL L/D ratio decreased curvilinearly with increasing daily dose of HAL. The patients treated with concomitant antiparkinsonian drugs showed a mean HAL L/D ratio that was 24.9% higher than those without antiparkinsonian drugs. The patients treated with concomitant antiepileptic drugs showed a mean HAL L/D ratio that was 27.2% lower than those without antiepileptic drugs. The mean HAL L/D ratio of patients treated with concomitant CYP2D6 substrates was not significantly different from those without CYP2D6 substrates. There is a wide interindividual variability in blood levels of HAL in patients given the same dose. Routine monitoring of HAL serum level is useful, especially in patients who require associated antiepileptic and/or antiparkinsonian medication.

Population pharmacokinetics of haloperidol using routine clinical pharmacokinetic data in Japanese patients.

To clarify the observed variability of haloperidol disposition in patients with psychiatric disorders. Retrospective population pharmacokinetic study. 218 Japanese patients aged 16 to 82 years who provided 391 serum haloperidol concentrations. Routine clinical pharmacokinetic data gathered from patients receiving haloperidol were analysed to estimate population pharmacokinetic parameters with the nonlinear mixed effects model (NONMEM) computer program. The final pharmacokinetic model was CL = 42.4 * (TBW/60)(0.655) * 0.814(AGE> or = 55) * (DOSE/200)(0.236) * 1.32(ANTIEP) and Vd = 34.4 * TBW * 0.336( AGE> or = 65), where CL is total body clearance (L/h), Vd is apparent volume of distribution (L), TBW is total bodyweight (kg), DOSE is daily dosage (microg/kg/day), ANTIEP = 1 for concomitant administration of antiepileptic drugs (phenobarbital, phenytoin or carbamazepine) and 0 otherwise, AGE > or = 55 = 1 for patient aged 55 years or over and 0 otherwise, and AGE > or = 65 = 1 for patient aged 65 years or over and 0 otherwise. Concomitant administration of haloperidol and antiepileptic drugs resulted in a 32% increase in haloperidol clearance. Patients aged 55 years or over showed an 18.6% reduction in clearance, and elderly patients aged 65 years or over showed a 66.4% reduction in apparent volume of distribution. Inclusion of terms for the concomitant administration of haloperidol and antiparkinsonian drugs (amantadine, bromocriptine, biperiden, trihexyphenidyl or mazaticol) or cytochrome P450 (CYP) 2D6 substrates (levomepromazine, perphenazine, thioridazine, amitriptyline or clomipramine) did not significantly improve the estimate of haloperidol clearance. Application of the findings in this study to patient care may permit selection of an appropriate initial maintenance dosage to achieve target haloperidol serum concentrations, thus enabling the clinician to achieve the desired therapeutic effect.

Factors affecting serum haloperidol level assessed by longitudinal therapeutic monitoring

1. 1. Since the development of a kit for the assay of haloperidol by enzyme immunoassay, therapeutic monitoring of haloperidol has been utilised in Japan for several years. By retrospectively analysing the accumulated data, this study was carried out to investigate the factors affecting haloperidol level. Especially, the effects of enzyme-inducing comedications were analysed in relation to serum gamma-glutamyltransferase (GGT) level, which has been measured simultaneously with haloperidol. 2. 2. Serum haloperidol level measurements were obtained from medical records of inpatients on multiple medications ( n = 102). For each subject, average haloperidol level was computed during the same prescription and doses. The effects of age, sex, smoking status, and the coadministration of carbamazepine and barbiturates (including phenobarbital, amobarbital and pentobarbital) were analysed using correlation, between-group comparison and multiple regression analysis. Separately, the effect of comedications on haloperidol and GGT levels were analysed individually in a small number of patients ( n = 5) who had received those comedications intermittently. 3. 3. Significant lowering of serum haloperidol level by the coadministration of carbamazepine and/or barbiturates was observed. The coadministration was also correlated with the elevated GGT level in between-group comparison. In the separate analysis, the change in haloperidol level was correlated with the change in GGT level in some individuals but not in others. None of the other clinical factors investigated in the study showed significant effect on haloperidol level. 4. 4. This study suggests that the lowering of haloperidol level and the elevation of GGT level may often occur coincidentally by the coadministration of enzyme-inducing drugs. However, whether there is a causal relationship between these phenomena and whether elevated serum GGT level could serve as a clinically useful marker need to be clarified by further basic pharmacological research.

Association between a polymorphism in the promoter region of the dopamine D2 receptor gene and schizophrenia in Japanese subjects: replication and evaluation for antipsychotic-related features.

To replicate a previously found negative association between the Del allele of the -141C Ins/Del polymorphism in the 5'-promoter region of the dopamine D2 receptor gene (DRD2) and schizophrenia in Japanese subjects and to examine whether this polymorphism is related to the features of antipsychotic drug treatment, we genotyped 94 control subjects and 234 schizophrenic patients. The schizophrenic patients had a significantly lower frequency of the Del allele (p < 0.05). We found a non-significant trend towards a higher frequency of the Del allele in schizophrenic patients susceptible to neuroleptic-induced extrapyramidal symptoms. The daily dosage of haloperidol, the steady-state concentration of serum haloperidol per daily dosage, and the recent 1-yr cumulative neuroleptic dosage were lower in patients with the Del/Del genotype than in the other patients. These findings support the view that the polymorphism is associated with schizophrenia in Japanese subjects and provide hints for further attempts to establish the relationship between this polymorphism and the features of antipsychotic drug treatment.

Neuroleptic monitoring: relation between antipsychotic efficiency and radioreceptor assay of serum haloperidol.

We report preliminary results from use of a radioreceptor assay (RRA) to measure serum haloperidol levels and their relation to clinical response and adverse effects in 19 psychotic patients with positive symptoms treated with haloperidol. Blood samples were taken on Days 7, 14 and 21. Clinical evaluation was based on the PANSS, and UKU scales. The D2 antidopaminergic RRA was used to measure haloperidol serum levels. Our results show a correlation between psychosis with positive symptoms assessed by positive scores in the PANSS and the serum drug level measured by RRA concentrations. The observed relationship made it possible to establish a therapeutic serum range of haloperidol equivalents 15-30 ng/ml-1. This range contained no "non-responders". Analysis of the correlation between each item on the positive subscale of the PANSS and the RRA concentration suggested that there was no specific symptom of psychosis closely related to RRA concentration during the first 15 days of treatment. In the third week, however, certain specific symptoms were closely connected to the RRA concentration. From these results, it can be concluded that antipsychotic activity can be related to blockade of serum D2 dopamine receptors. In future would be desirable to monitor neuroleptic treatment in this way. The study also showed that the antipsychotic treatment did not correct any specific component of the psychosis during the first stage of the treatment but that it did so at later times.

Acute versus chronic haloperidol: relationship between tolerance to catalepsy and striatal and accumbens dopamine, GABA and acetylcholine release

Using in vivo microdialysis, changes in extracellular dorsolateral striatum and nucleus accumbens dopamine, GABA and acetylcholine following acute and chronic haloperidol (0.25 mg/kg, s.c.) were evaluated in rats concurrent with the measurement of catalepsy. When administered to drug-naive and chronically treated rats, haloperidol was associated with a consistent and prolonged (> 150 min) increase in dorsolateral striatum and nucleus accumbens DA release and a transient (60 min) increase in dorsolateral striatum GABA release. Haloperidol was also associated with a transient (30 min) increase in dorsolateral striatum acetylcholine release in the chronically treated rats. Basal dopamine and acetylcholine levels were similar in both brain regions; however, basal dorsolateral striatum GABA levels were two-fold higher in the chronically treated rats. Administration of haloperidol was associated with a prolonged (> 150 min) catalepsy in the drug-naive rats which was greatly diminished or absent in chronically treated rats. Additionally, serum haloperidol levels were shown to be similar 120 min following administration of haloperidol in both groups. These results indicate a marked behavioral difference in the effects of haloperidol in drug-naive and chronically treated rats which is not related to an altered bioavailability of the drug and which is dissociated from both basal and haloperidol induced effects on dopamine and acetylcholine release in both brain regions. However, the selective elevation of basal dorsolateral striatum GABA release following chronic administration of haloperidol may contribute to the development of tolerance to catalepsy as well as providing an in vivo neurochemical marker of the long-term effects of haloperidol.

Acute accidental overdosage of haloperidol in children

We report the details of an accidental overdosage of haloperidol in 24 children in one hospital in Kyushu, Japan. Evidence of acute toxicity included disturbances in consciousness (24/24), tremors in the extremities (16/24), an oculogyric or similar crisis (14/24), dysarthria (9/17), drooling (8/24), akathisia (6/20), hyperreflexia (6/24) and opisthotonos (3/24). Laboratory examinations revealed late‐onset transient thrombocytosis (5/24), elevated AST and GPT (1/24) and abnormal ECG with prolonged QT interval in 2 of 8 children. We detected haloperidol in 11 of 18 children whose blood was specifically examined within four days after the final haloperidol administration. The maximum serum haloperidol level was 28.9 ng/ml. The mean half‐life of haloperidol in the serum of five children (age range 2–10 years) was 18.6 ± 12.2 h (mean ± SD) (range 9.1–39.4 h).

Acute accidental overdosage of haloperidol in children.

We report the details of an accidental overdosage of haloperidol in 24 children in one hospital in Kyushu, Japan. Evidence of acute toxicity included disturbances in consciousness (24/24), tremors in the extremities (16/24), an oculogyric or similar crisis (14/24), dysarthria (9/17), drooling (8/24), akathisia (6/20), hyperreflexia (6/24) and opisthotonos (3/24). Laboratory examinations revealed late-onset transient thrombocytosis (5/24), elevated AST and GPT (1/24) and abnormal ECG with prolonged QT interval in 2 of 8 children. We detected haloperidol in 11 of 18 children whose blood was specifically examined within four days after the final haloperidol administration. The maximum serum haloperidol level was 28.9 ng/ml. The mean half-life of haloperidol in the serum of five children (age range 2-10 years) was 18.6 +/- 12.2 h (mean +/- SD) (range 9.1-39.4 h).

The relationship between serum haloperidol, smoking, and tardive dyskinesia (TD) : Vikram Khot, M.D., Esa R. Korpi, M.D., Diane Venable, B.S., Richard Jed Wyatt, M.D., Darrell Kirch, M.D. National Institute of Mental Health Neurosciences Center at St. Elizabeth's, Washington, D.C. 20032

The relationship between serum haloperidol, smoking, and tardive dyskinesia (TD) : Vikram Khot, M.D., Esa R. Korpi, M.D., Diane Venable, B.S., Richard Jed Wyatt, M.D., Darrell Kirch, M.D. National Institute of Mental Health Neurosciences Center at St. Elizabeth's, Washington, D.C. 20032

Direct Radioimmunoassay for Haloperidol in Human Serum

A direct radioimmunoassay for the accurate determination of haloperidol in human serum has been developed. Based on recent information about the metabolism of haloperidol, a new haloperidol hapten, in which a (3-carboxypropionyl)methylamino group was attached as a bridge in the place of fluorine atom, was synthesized and coupled to bovine serum albumin through the bridge to provide a new immunogen. Guinea pigs were used for the immunization. Since the antisera obtained by the new immunogen still cross reacted >10% with reduced haloperidol, the immunological tolerance to reduced haloperidol was induced by administration of a copolymer of D-glutamic acid and D-lysine linked with reduced haloperidol. This gave an antiserum in guinea pigs which was highly specific for unchanged haloperidol with negligible cross reactivity (≤1.0%) to any haloperidol metabolites including the newly found ones. With the newly developed antiserum and [3H]haloperidol, serum haloperidol levels can be determined over the concentration range from 0.3 to 20 ng/mL, using 0.1mL of human serum, without an extraction procedure.

Change in Haloperidol Level Due to Carbamazepine???A Complicating Factor in Combined Medication for Schizophrenia

Serum haloperidol levels were measured in patients who received haloperidol alone and, subsequently, haloperidol in combination with carbamazepine or lithium carbonate. Haloperidol levels and the level- dose ratios dropped about 50% in patients receiving carbamazepine. They remained the same in most patients receiving lithium carbonate. One patient receiving added carbamazepine experienced worsening of symptoms; this was associated with a drop in serum haloperidol level. Two other patients receiving added carbamazepine showed significant symptom reduction, although they also sustained drops in serum haloperidol levels. It is not clear whether these two individuals benefited from a primary antipsychotic effect of carbamazepine or from reduction of "toxic" haloperidol levels. Serum levels of antipsychotic medication should be monitored carefully when these medications are prescribed in combination with carbamazepine.

Serum haloperidol and anticholinergic levels in drug-induced parkinsonism

Serum haloperidol and anticholinergic levels in drug-induced parkinsonism

Substantial rise in sparteine metabolic ratio during haloperidol treatment.

A sparteine test was carried out in 14 patients suffering from acute schizophrenic psychoses before and 1-2 times during oral haloperidol treatment in doses of 10-40 mg day-1. In patients classified as extensive metabolisers (sparteine MR less than 20 before treatment), haloperidol treatment resulted in a rise in sparteine MR that correlated with the serum-haloperidol concentration both within and between patients. At the highest serum haloperidol concentrations (60-80 nM) an increase in sparteine MR by a factor 15-50 was seen, but no patients were transformed into phenotypically poor metabolisers. The steady state concentration of haloperidol on the initial standard dose of 10 mg day-1 was the same in one patient classified as a sparteine poor metaboliser (MR = 112) as in eleven patients classified as extensive metabolisers (MR:0.22-1.47).

Haloperidol and Prolactin Concentrations in Asians and Caucasians

Serum haloperidol and prolactin concentrations were measured in 34 normal male volunteers (12 Caucasians, 11 American-born Asians, and 11 foreign-born Asians) over a 7-hour period after haloperidol administration (0.5 mg given intramuscularly or 1.0 mg given orally). The results were similar between the two Asian groups but significantly different between Caucasians and Asians. After controlling for body surface area, Caucasians still had lower serum haloperidol concentrations and less prominent prolactin responses than did Asians. Furthermore, the ethnic difference in prolactin responses could not be fully accounted for by the differences in serum haloperidol concentrations between the two ethnic groups. These results indicate that both pharmacokinetic factors, including absorption and hepatic first-pass metabolism, and pharmacodynamic factors (dopamine receptor-mediated responses) contribute to the difference in responses between Caucasians and Asians.

Serum haloperidol levels and clinical response in chronic, treatment-resistant schizophrenic patients

Eleven chronic treatment-resistant schizophrenic in-patients were treated with haloperidol (HPL) or placebo with a fixed ascending dose schedule for 20 weeks. Seven patients relapsed and were withdrawn and five of these re-entered, single-blind, on known active treatment. Two weekly clinical ratings and weekly serum HPL levels were carried out throughout the study. More patients on placebo dropped out and at an earlier stage than those on active treatment but the difference was not statistically significant. Despite wide individual variations in both serum HPL levels and clinical response, these were positively correlated. HPL appeared to be of more value in the prevention of relapse than in symptom reduction. Overall, the clinical response was poor and a 'therapeutic window' could not be demonstrated either for the group as a whole or in any individual patient. There was no additional therapeutic benefit in exceeding serum HPL levels of 20 ng/ml in any of our patients. Since this serum level was achieved by daily doses of 10-40 mg HPL and the relationship between dose and serum level is linear, the use of serum HPL estimations is not likely to be of value in the routine clinical management of treatment-resistant patients.