Plasma Concentrations Of Haloperidol Research Articles

Racial/Ethnic Differences in the Pharmacokinetics of Antipsychotics: Focusing on East Asians.

Empirical clinical studies have suggested that East Asian patients may require lower dosages of psychotropic drugs, such as antipsychotics, lithium, and antidepressants, than non-Asians. Both the pharmacokinetic and pharmacodynamic properties of a drug can affect the clinical response of an illness. The levels of antipsychotics used for the treatment of schizophrenia may affect patient clinical responses; several factors can affect these levels, including patient medication adherence, body weight (BW) or body mass index, smoking habits, and sex. The cytochrome P450 (CYP) system is a major factor affecting the blood levels of antipsychotics because many antipsychotics are metabolized by this system. There were notable genetic differences between people of different races. In this study, we determined the racial or ethnic differences in the metabolic patterns of some selected antipsychotics by reviewing therapeutic drug monitoring studies in East Asian populations. The plasma concentrations of haloperidol, clozapine, quetiapine, aripiprazole, and lurasidone, which are metabolized by specific CYP enzymes, were determined to be higher, under the same daily dose, in East Asian populations than in Western populations.

Monitoring Haloperidol Plasma Concentration and Associated Adverse Events in Critically Ill Children With Delirium: First Results of a Clinical Protocol Aimed to Monitor Efficacy and Safety.

As delirium in critically ill children is increasingly recognized, more children are treated with the antipsychotic drug haloperidol, while current dosing guidelines are lacking solid evidence and appear to be associated with a high risk of adverse events. We aim to report on the safety and efficacy of a recently implemented clinical dose-titration protocol with active monitoring of adverse events. From July 2014 until June 2015, when a potential delirium was identified by regular delirium scores and confirmed by a child psychiatrist, haloperidol was prescribed according to the Dutch Pediatric Formulary. Daily, adverse events were systematically assessed, haloperidol plasma concentrations were measured, and delirium symptoms followed. Dependent on the clinical response, plasma concentration, and adverse event, the dose was adjusted. A 28-bed tertiary PICU in the Netherlands. All patients admitted to the PICU diagnosed with delirium. Treatment with haloperidol according to a dose-titration protocol MEASUREMENTS AND MAIN RESULTS:: Thirteen children (median age [range] 8.3 yr [0.4-13.8 yr]) received haloperidol, predominantly IV (median dose [range] 0.027 mg/kg/d [0.005-0.085 mg/kg/d]). In all patients, pediatric delirium resolved, but five of 13 patients developed possible adverse event. These were reversed after biperiden (n = 2), discontinuing (n = 3), and/or lowering the dose (n = 3). Plasma concentrations were all below the presumed therapeutic threshold of 3-12 µg/L. Prospective systematic monitoring of adverse event in critically ill children receiving haloperidol revealed a significant proportion of possible adverse events. Adverse event developed despite low plasma concentrations and recommended dose administration in the majority of the patients. Our data suggest that haloperidol can potentially improve pediatric delirium, but it might also put patients at risk for developing adverse events.

Investigation of the synergistic effects of haloperidol combined with Calculus Bovis Sativus in treating MK-801-induced schizophrenia in rats.

Clinical studies that focused on treating schizophrenia showed that Calculus Bovis Sativus (CBS), a substitute of Calculus Bovis, when used in combination with haloperidol could significantly lower the dosage of haloperidol compared with treatment with haloperidol alone, whereas efficacy was maintained. The aim of this study was to investigate the synergetic anti-schizophrenia effects in rats using CBS in combination with haloperidol. An open field test was conducted to verify the pharmacodynamic effects of a combination treatment of CBS and haloperidol on MK-801-induced schizophrenic rats. Rat plasma concentrations of intragastric haloperidol and intravenous haloperidol were determined after oral administration of a single dose or 1-week of pretreatment with CBS (50 mg/kg). The pharmacodynamic data showed a significant decrease in locomotor activity and an increase in the percentage of the central distance when haloperidol was concomitantly administered with CBS compared with haloperidol administration alone. The AUC0-∞ and Cmax of haloperidol in the orally coadministered groups were significantly higher compared with the oral treatment with haloperidol alone. In conclusion, oral coadministration of CBS with haloperidol resulted in a synergistic effect in rats. The enhanced oral bioavailability of haloperidol when combined with CBS might be attributed to the interaction between them.

Genotyping and phenotyping of CYP2D6 and CYP3A isoenzymes in patients with alcohol use disorder: correlation with haloperidol plasma concentration.

Haloperidol is used for the treatment of alcohol use disorders in patients with signs of alcohol-related psychosis. Haloperidol therapy poses a high risk of adverse drug reactions (ADR). Contradictory data, which include the effects of genetic polymorphisms in genes encoding the elements of haloperidol biotransformation system on haloperidol metabolism rate and plasma drug concentration ratio, are described in patients with different genotypes. The primary objective of this study was to investigate the effects of CYP2D6 and CYP3A5 genetic polymorphisms on haloperidol equilibrium concentration in patients with alcohol use disorder. The study included 69 male patients with alcohol use disorder. Genotyping was performed using the allele-specific real-time PCR. CYP2D6 and CYP3A were phenotyped with HPLC-MS using the concentration of endogenous substrate of the enzyme and its urinary metabolites [6-hydroxy-1,2,3,4-tetrahydro-β-carboline(6-HO-THBC) to pinoline ratio for CYP2D6 and 6-β-hydroxycortisol to cortisol ratio for CYP3A]. The equilibrium plasma concentration was determined using LC-MS-MS. Results indicated that both C/D indexes and equilibrium concentration levels depend on CYP2D6 genetic polymorphism, but only in patients receiving haloperidol intramuscular injections [0.26 (0.09; 0.48) vs. 0.54 (0.44; 0.74), p=0.037]. The study demonstrates that CYP2D6 genetic polymorphism (1846G>A) can affect haloperidol concentration levels in patients with alcohol use disorder.

Supra-therapeutic plasma concentrations of haloperidol induce moderate inhibition of lipopolysaccharide-induced interleukin-8 release in human monocytes.

The clinical use of antipsychotics and mood-stabilizing drugs with proven efficacy is largely determined by the occurrence of treatment-emergent adverse events and routine clinical chemistry and haematology data, which together define the safety and tolerability profile of these psychopharmaceuticals. Whereas the effects of mood-stabilizing drugs on functional properties of blood cells have been poorly investigated, the effects of antipsychotics have received more attention. Such studies have yielded conflicting results. This study examined the effects of the mood-stabilizing drugs carbamazepine and valproic acid and of the antipsychotic drugs olanzapine, risperidone and haloperidol on the production of the pro-inflammatory chemokine interleukin-8 (IL-8), which is released from human monocytes when activated by Gram-negative lipopolysaccharide (LPS). Peripheral human whole blood was diluted with Roswell Park Memorial Institute (RPMI) cell culture medium and stimulated with LPS. Accumulating IL-8 was quantified in the supernatant with an adapted enzyme-linked immunosorbent assay (ELISA) and the results correlated to the number of monocytes at venipuncture. At supra-therapeutic concentrations of 100 µM, haloperidol inhibited the LPS-induced release of IL-8 in peripheral human monocytes moderately, whereas olanzapine, risperidone, carbamazepine and valproic acid showed no such effect. The results suggest that these mood-stabilizing drugs and antipsychotics are endowed with clinically favorable inertness rather than pro-inflammatory properties.

Lack of correlation between the steady-state plasma concentrations of aripiprazole and haloperidol in Japanese patients with schizophrenia.

Both aripiprazole and haloperidol have been used in the treatment of schizophrenia, and are metabolized by the cytochrome P450 (CYP) 2D6 and CYP3A4. The authors studied the correlations between the steady-state plasma concentrations (Css) of aripiprazole and its active metabolite, dehydroaripiprazole, and those of haloperidol in 19 Japanese patients with schizophrenia, together with the effects of CYP2D6 genotypes on the steady-state kinetics of these compounds. All the patients received first 24 mg/d of aripiprazole for 3 weeks and later received 6 mg/d of haloperidol for 2 weeks. Blood samplings were performed at least 2 weeks after the initiation of each treatment. The Css values of aripiprazole and dehydroaripiprazole were measured using liquid chromatography with mass spectrometric detection, and those of haloperidol were measured by using an enzyme immunoassay. CYP2D6 genotypes were determined by using polymerase chain reaction analysis. None of the correlations between the Css of aripiprazole (r = 0.286) or the sum of aripiprazole plus dehydroaripiprazole (r = 0.344) and those of haloperidol were significant. The mean Css of aripiprazole was significantly higher (P < 0.05) in the subjects with 1 *10 allele of CYP2D6 (n = 6) than in those with no mutated alleles (n = 13), whereas there were no significant differences in those of haloperidol between the 2 groups. This study suggests that the Css of aripiprazole and that of aripiprazole plus dehydroaripiprazole do not correlate with that of haloperidol in the same individual, because of the greater involvement of CYP2D6 in the metabolism of aripiprazole than in that of haloperidol.

Population Pharmacokinetic-Pharmacodynamic Modeling of Haloperidol in Patients With Schizophrenia Using Positive and Negative Syndrome Rating Scale

The aim of this study was to develop a pharmacokinetic-pharmacodynamic (PKPD) model that quantifies the efficacy of haloperidol, accounting for the placebo effect, the variability in exposure-response, and the dropouts. Subsequently, the developed model was utilized to characterize an effective dosing strategy for using haloperidol as a comparator drug in future antipsychotic drug trials. The time course of plasma haloperidol concentrations from 122 subjects and the Positive and Negative Syndrome Scale (PANSS) scores from 473 subjects were used in this analysis. A nonlinear mixed-effects modeling approach was utilized to describe the time course of PK and PANSS scores. Bootstrapping and simulation-based methods were used for the model evaluation. A 2-compartment model adequately described the haloperidol PK profiles. The Weibull and Emax models were able to describe the time course of the placebo and the drug effects, respectively. An exponential model was used to account for dropouts. Joint modeling of the PKPD model with dropout model indicated that the probability of patients dropping out is associated with the observed high PANSS score. The model evaluation results confirmed that the precision and accuracy of parameter estimates are acceptable. Based on the PKPD analysis, the recommended oral dose of haloperidol to achieve a 30% reduction in PANSS score from baseline is 5.6 mg/d, and the corresponding steady-state effective plasma haloperidol exposure is 2.7 ng/mL. In conclusion, the developed model describes the time course of PANSS scores adequately, and a recommendation of haloperidol dose was derived for future antipsychotic drug trials.

Exploration of Optimal Dosing Regimens of Haloperidol, a D2 Antagonist, via Modeling and Simulation Analysis in a D2 Receptor Occupancy Study

To evaluate the potential usage of D(2) receptor occupancy (D2RO) measured by positron emission tomography (PET) in antipsychotic development. In this randomized, parallel group study, eight healthy male volunteers received oral doses of 0.5 (n = 3), 1 (n = 2), or 3mg (n = 3) of haloperidol once daily for 7days. PET's were scanned before haloperidol, and on days 8, 12, with serial pharmacokinetic sampling on day 7. Pharmacokinetics and binding potential to D(2) receptor in putamen and caudate nucleus over time were analyzed using NONMEM, and simulations for the profiles of D2RO over time on various regimens of haloperidol were conducted to find the optimal dosing regimens. One compartment model with a saturable binding compartment, and inhibitory E(max) model in the effect compartment best described the data. Plasma haloperidol concentrations at half-maximal inhibition were 0.791 and 0.650ng/ml, in putamen and caudate nucleus. Simulation suggested haloperidol 2mg every 12h is near the optimal dose. This study showed that sparse D2RO measurements in steady state pharmacodynamic design after multiple dosing could reveal the possibility of treatment effect of D(2) antagonist, and could identify the potential optimal doses for later clinical studies by modeling and simulation.

Parkinsonism in Elderly Users of Haloperidol

Factors that influence the variation in occurrence of antipsychotic-induced parkinsonism (AIP) in the elderly have not been well elucidated. The aim of this study was to investigate the association between parkinsonism in elderly users of haloperidol and prescribed dose, plasma concentration, and duration of use of haloperidol in a cross-sectional design. This study included 150 inpatients aged 65 years and older who were treated with haloperidol. Parkinsonism assessed by the Simpson Angus Scale was present in 46% of the included patients. Prescribed haloperidol dose varied from 0.3 to 5 mg/d. Plasma concentration ranged from 0.13 to 4.11 μg/L, with one outlying measurement (21.43 μg/L). Dose is moderate but significantly associated with haloperidol plasma concentration (weighted R2 = 0.32; P < 0.001). Variability in the total score on the Simpson Angus Scale could not be explained by the variability in dose, concentration (respectively R2 = 0.003 and 0.001) nor duration of use of haloperidol. Smoking showed to be not significantly protective in the development of AIP (crude odds ratio, 0.39; 95% confidence interval, 0.15-0.997; and adjusted odds ratio, 0.44; 95% confidence interval, 0.17-1.17). In a clinical practice-setting dose, neither plasma concentration nor duration of use of haloperidol is associated with an increased occurrence of AIP. This study does not support the hypothesis of the peripheral pharmacokinetic explanation for the high prevalence of AIP and differences in AIP sensitivity in the elderly during treatment with haloperidol.

Bioavailability and In-vivo Transdermal Delivery of Haloperidol

Background: Sustained blood level with effective therapeutic blood level inpsychotic patients in the range of usual therapeutic dose is favorable.Objectives: To investigate where this sustained and effective therapeutic blood level and improve in bioavailability could be achieved by usinghaloperidol/transdermal gel formulation.Materials and Methods: In-vivo transdermal delivery of haloperidol wasstudied in rabbits comparing transdermal gel formulation containing 1, 8-cineole as penetration enhancer and oral tablet. Concentrations of haloperidol in plasma were measured by reverse phase HPLC. The pharmacokinetic parameters generated from this study were evaluatedstatistically using one-way analysis of variance (ANOVA).Result: The results showed that transdermal gel formulation increased rate and extent of absorption and improve bioavailability of haloperidol. The plasma concentrations of haloperidol were declined in biexponential fashion where the area under the curves and absorption rate Cmax/AUC elimination rate constant Kel, Tmax, mean residence time (MRT), mean absorption time (MAT), and total clearance (CLtotal) were significantly different p < 0.05, but volume of distribution (Vd) did not differ significantly p >0.05.The absolute bioavailability from the oral tablet, and the transdermal formulation was 38% and 57% respectively and highly significant P < 0.01.Conclusion: This study suggest that it is possible to achieve significant sustained therapeutic blood levels for longer time and also suggest that further human investigations of the transdermal dosage are warranted.Key words: Haloperidol/Transdermal gel formulation, Oral tablet, Rabbits, Bioavailability,Pharmacokinetic.

Role of CYP2D6 gene polymorphism in individual's ability to quit smoking

In 1980, we published two papers of importance for the future of our research: (i) it was shown that the two polymorphic hydroxylations of debrisoquine and sparteine are catalysed by a common enzyme now called CYP2D6 and (ii) that this polymorphic enzyme also catalysed the metabolism of the tricyclic antidepressant nortriptyline. Later, it was shown that most antidepressants are metabolized by CYP2D6. There are many allelic variants of CYP2D6 causing decreased (e.g. CYP2D6*10 in Asians) or no (*4 in Caucasians) activity of the enzyme. We have identified duplication and amplification of a CYP2D6 gene as a cause of ultrarapid metabolism. There are pronounced interethnic differences in these allelic variants. When nortriptyline was given as single doses to healthy subjects, there was a close relationship between the rate of 10-hydroxylation and the number of functional CYP2D6 genes.Most neuroleptic drugs are also metabolized by CYP2D6. Exceptions are the atypical neuroleptics clozapine and olanzapine, which are mainly metabolized by CYP1A2. When haloperidol was given as a single oral dose to a panel of healthy Swedish Caucasians, PM of debrisoquine eliminated the drug slower than EM (PM=poor, EM=extensive metabolisers). Among eight patients treated with i.m. injection of haloperidol decanoate every 4 weeks, one patient having the genotype CYP2D6*4/*4 and thus a PM, had the highest plasma concentration of haloperidol, highest dopamine D2-receptor occupancy and most pronounced extrapyramidal side-effects. In Japan, plasma concentrations of haloperidol per dose unit have been shown to be related to the CYP2D6*10 allele. In Koreans, this relationship was confirmed at doses of haloperidol below 20 mg per day, but not at higher doses. These and other studies taken together show that at low doses haloperidol is metabolized by CYP2D6, while at high doses, this enzyme is saturated and then enzymes with a higher capacity, e.g. CYP3A4, are taking over.CYP2D6 catalyzes the metabolism of a large number of psychotropic drugs and the pronounced variation in its activity between individuals and populations contributes to the variation in treatment response and side effects. Also, it must be emphasized that when two drugs, both of which are substrates of CYP2D6, are co-administrated they may increase each others' plasma concentrations and potentiate therapeutic effects and adverse drug reactions.

Depot Haloperidol Treatment in Outpatients With Schizophrenia on Monotherapy: Impact of CYP2D6 Polymorphism on Pharmacokinetics and Treatment Outcome

Haloperidol and several other antipsychotic drugs are at least partially metabolized by the polymorphic cytochrome P450 2D6 (CYP2D6). The interindividual variation in metabolic capacity of CYP2D6 might be of importance when dosing. In this study, 26 outpatients with schizophrenia and depot haloperidol as monotherapy were genotyped. The authors found 1 patient with no functional alleles, 8 with one functional allele, 16 with two functional alleles, and 1 with three functional alleles. The daily dose of haloperidol ranged from 0.45 to 14.29 mg. Steady state plasma concentrations were measured at peak (range, 1.6-67 nmol/L) and at trough (range, 1.0-49 nmol/L). The Positive and Negative Syndrome scale for Schizophrenia and the Extrapyramidal Symptom Rating Scale were used to evaluate the clinical effect. The authors found a clear correlation between haloperidol plasma concentration and number of active CYP2D6 alleles. No correlation was found between plasma concentration of haloperidol or number of CYP2D6 alleles and treatment outcome or side effects. A model to predict plasma concentration from dose and number of active CYP2D6 alleles was formed from the obtained data by means of multiple linear regression.

Pharmacokinetics and bioequivalence of haloperidol tablet by liquid chromatographic mass spectrometry with electrospray ionization

The purpose of this study is to investigate the bioequivalence of two haloperidol 5 mg tablets, Myung In haloperidol (Myung In Pharm. Co., Ltd., test drug) and Peridol (Whanin Pharm. Co., Ltd., reference drug), and also to estimate the pharmacokinetic parameters of haloperidol in Korean volunteers. The bioavailability and pharmacokinetics of haloperidol tablets were examined on 24 healthy volunteers who received a single oral dose of each preparation in the fasting state in a randomized balanced 2 way crossover design. After an oral dosing, blood samples were collected for a period of 60 h. Plasma concentrations of haloperidol were determined using a liquid chromatographic electrospray mass spectrometric (LC-MS) method. The pharmacokinetic parameters were calculated with noncompartmental pharmacokinetic analysis. The geometric means of AUC0-60h and Cmax between test and reference formulations were 17.21 +/- 8.26 ng x h/mL vs 17.31 +/- 13.24 ng x h/mL and 0.87 +/- 0.74 ng/mL vs 0.85 +/- 0.62 ng/mL, respectively. The 90% confidence intervals of mean difference of logarithmic transformed AUC0-60h and Cmax were log0.9677 - log1.1201 and log0.8208-log1.1981, respectively. It shows that the bioavailability of test drug is equivalent with that of reference drug. The geometric means of other pharmacokinetic parameters (AUCinf, t1/2, Vd/F, and CL/F) between test drug and reference drug were 21.75 +/- 8.50 ng x h/mL vs 21.77 +/- 15.63 ng x h/mL, 29.87 +/- 8.25 h vs 29.60 +/- 7.56 h, 11.51 +/- 5.45 L vs 12.90 +/- 6.12 L and 0.26 +/- 0.09 L/h vs 0.31 +/- 0.17 L/h, respectively. These observations indicate that the two formulation for haloperidol was bioequivalent and, thus, may be clinically interchangeable.

QT PRODACT: Usability of Miniature Pigs in Safety Pharmacology Studies: Assessment for Drug-Induced QT Interval Prolongation

To investigate whether miniature pigs are useful for evaluating the potential of drugs for drug-induced prolongation of the QT interval, we performed an in vivo QT assay using conscious and unrestricted miniature pigs. Compared with the vehicle average baseline values, haloperidol at 3 and 10 mg/kg, p.o. prolonged the QTcF interval (Fridericia’s formula) by 8% – 16%. The plasma concentration of haloperidol at which QT interval was prolonged (Cmax = 42.9 ng/mL) was almost equal to that in humans. dl-Propranolol at 3, 10, and 30 mg/kg, p.o. caused no alterations in QT interval. dl-Propranolol at 3, 10, and 30 mg/kg, at which plasma concentrations were lower than in humans treated with dl-propranolol at the therapeutic dose level, shortened QTcF interval by 7% – 12%. dl-Sotalol at 10 mg/kg, p.o. prolonged QTcF interval by 7%. From the above results, we considered that the miniature pig can be used for prediction of drug-induced prolongation of QT interval in humans, and thus, it is one of the useful animal species for assessing electrocardiograms in safety pharmacology studies.

Poor reliability of therapeutic drug monitoring data for haloperidol and bromperidol using enzyme immunoassay.

Therapeutic drug monitoring (TDM) services for plasma concentrations of haloperidol and bromperidol using enzyme immunoassay (EIA) methods are available in Japan, whereas high-performance liquid chromatographic (HPLC) methods are preferred in other countries. To compare these methods, we took 54 plasma samples for haloperidol and 91 plasma samples for bromperidol from schizophrenic patients receiving haloperidol or bromperidol, and the samples were measured using both commercial EIA and HPLC methods. Significant linear correlations were found between the two methods in determining haloperidol (EIA = 1.351 x HPLC + 1.39; r = 0.934, P < 0.001) and bromperidol (EIA = 1.420 x HPLC + 0.712; r = 0.956, P < 0.001) concentrations, but plasma concentrations using the EIA kits were approximately 92% (95% CI; 53-131%) and 62% (54-70%) higher than those using HPLC for haloperidol and bromperidol, respectively. Mean (and range) plasma concentrations of reduced metabolites were 54% (30-92%) and 55% (29-111%) of those of haloperidol and bromperidol, respectively. The present study suggests that reduced metabolites are included to a considerable degree in TDM data using the EIA kits. Therefore, some limitation of TDM data of haloperidol and bromperidol using the EIA kits, ie, high precision but poor accuracy, should be kept in mind.

Significant Dose Effect of Carbamazepine on Reduction of Steady-State Plasma Concentration of Haloperidol in Schizophrenic Patients

A reduction in haloperidol concentration induced by carbamazepine coadministration has been consistently reported. However, the degree of this reduction is very different among individuals treated with various doses of carbamazepine. Thus, we investigated dose effect of carbamazepine on the steady-state plasma concentration of haloperidol. Eleven excited schizophrenic inpatients, despite receiving haloperidol 12 mg/d, were treated with incremental doses of carbamazepine for 6 weeks (100, 300, 600 mg/d for 2 weeks each). Plasma drug concentrations were monitored together with clinical assessments before and after each phase of the 3 carbamazepine doses. Mean haloperidol concentrations during coadministration of carbamazepine 100, 300, and 600 mg/d were 75%, 39%, and 15%, respectively, of corresponding variables before carbamazepine coadministration. Negative linear correlations were observed between dose or plasma concentration of carbamazepine and the degree of reduction in haloperidol concentration. Mean carbamazepine dose and plasma carbamazepine concentrations at 50% reduction of haloperidol concentration were 240 mg/d and 3.5 microg/mL, respectively. Scores in total and excitement symptoms were significantly reduced after carbamazepine coadministration, whereas no changes were observed in other clinical symptoms or any of the subgroup side effects. Therefore, this study indicates that carbamazepine decreases plasma haloperidol concentration in a dose-dependent or concentration-dependent manner, and that reduction in haloperidol concentration is apparent even at subtherapeutic dose of carbamazepine.

Haloperidol plasma concentration in Japanese psychiatric subjects with gene duplication of CYP2D6.

The cytochrome P-450 2D6 (CYP2D6) gene duplication/multiduplication producing an increase in enzyme activity, and the common Japanese mutation, CYP2D6*10A producing a decrease of enzyme activity were screened in a large number of Japanese psychiatric subjects (n = 111) in order to investigate whether these mutated alleles affected the plasma concentration of haloperidol. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was performed to identify the CYP2D6*10A and CYP2D6*2 genotypes in subjects who had been taking haloperidol. For the screening of duplicated active CYP2D6 gene, allele-specific long PCR was performed. Plasma concentration of haloperidol was measured by the enzyme immunoassay, and expressed as "plasma concentration dose ratio" to normalize individual differences. The plasma concentration-dose ratio showed large interindividual differences of approximately 18-fold. PCR-RFLP methods revealed that 29 (26.1%), 10 (9.0%), 39 (35.1%), 0 (0%), seven (6.3%) and 26 (23.4%) cases possessed the CYP2D6 genotypes *1/*1, *1/*2, *1/*10A, *2/*2, *2/*10A and *10 A/*10A, respectively. Six cases (5.4%) had duplicated CYP2D6 genes. There were no significant differences of plasma concentration-dose ratio between the groups classified by CYP2D6*10A and *2 genotypes (Kruskal-Wallis test; P = 0.37), even in those cases whose daily doses were lower than 20 mg (n = 90, P = 0.91). Subjects having duplicated genes (n = 6) did not show significant differences of plasma concentration-dose ratio by comparison with subjects who had no duplicated genes (Mann-Whitney U-test; P = 0.80). Gene duplication, and the common Japanese mutation CYP2D6*10A on CYP2D6 gene are not likely to be the main modulatory factors of plasma concentration of haloperidol in Japanese psychiatric subjects.

Effects of age and the CYP2D6∗10 allele on the plasma haloperidol concentration/dose ratio

The authors studied the effect of aging and the CYP2D6∗10 polymorphism on the plasma haloperidol (HAL) concentration after chronic administration of HAL. Subjects were 110 Japanese patients (66 male) treated orally with HAL. Venous blood was obtained from each patient for determination of the HAL concentration/dose (C/D) ratio (the plasma concentration of HAL divided by the daily dose of HAL per kilogram body weight) and for CYP2D6 genotyping. Overall, there was a significant linear correlation between the HAL C/D ratio and age. In subgroup analyses, the correlation was significant for patients with non-2D6∗10 homozygous genotypes, but not for those with the 2D6∗10 homozygous genotype. Overall, the HAL C/D ratio was significantly higher in older subjects (at least 50 years old) than younger ones (less than 50 years old). The ratio was significantly higher in older than in younger subjects for patients with non-2D6∗10 homozygous genotypes, but not for those with the 2D6∗10 homozygous genotype. Our results indicate that the effect of age on the HAL C/D ratio depends upon the CYP2D6∗10 genotype. Because there are racial differences in the CYP2D6 genotype, further studies should investigate age effects on the HAL C/D ratio in different patient populations.

Lack of Correlation between the Steady‐State Plasma Concentrations of Haloperidol and Risperidone

Both haloperidol and risperidone have been widely used in the treatment of schizophrenia. Because of wider therapeutic spectrum of risperidone, switching from haloperidol to risperidone is recommended in patients who do not sufficiently respond to haloperidol. The present study investigated the correlation between the steady‐state plasma concentrations of haloperidol and risperidone together with the effects of CYP2D6 status on the steady‐state kinetics of both drugs. Subjects were 22 schizophrenic inpatients. Eleven patients first received risperidone 6 mg/day and then haloperidol 12 mg/day, while the remaining 11 patients received these two treatments in the opposite sequence. The steady‐state plasma concentrations of risperidone, 9‐hydroxyrisperidone, haloperidol, and reduced haloperidol were measured after the subjects had been on the treatment for at least 2 weeks, and CYP2D6 genotypes were identified in all subjects. Neither the correlation between the steady‐state plasma concentrations of haloperidol and those of risperidone (r = 0.061, ns) nor the active moiety (sum of concentration of risperidone and 9‐hydroxyrisperidone) of risperidone (r = 0.141, ns) was significant. The mean (± SD) plasma concentration of risperidone in patients with mutated allele(s)forCYP2D6 was significantly higher than those without mutated allele (1.5 ± 0.7 vs. 8.5 ± 11.0, p&lt;0.05), while such a tendency for haloperidol was not observed. The present study suggests that the steady‐state plasma concentration of risperidone is not predicted from that of haloperidol in the same individual, probably because of the much greater involvement of CYP2D6 in the metabolism of risperidone than in that of haloperidol.

Clinical relevance of the CYP2D6 polymorphism for the treatment of psychiatric disorders

In 1980, we published two papers of importance for the future of our research: (i) it was shown that the two polymorphic hydroxylations of debrisoquine and sparteine are catalysed by a common enzyme now called CYP2D6 and (ii) that this polymorphic enzyme also catalysed the metabolism of the tricyclic antidepressant nortriptyline. Later, it was shown that most antidepressants are metabolized by CYP2D6. There are many allelic variants of CYP2D6 causing decreased (e.g. CYP2D6*10 in Asians) or no ( *4 in Caucasians) activity of the enzyme. We have identified duplication and amplification of a CYP2D6 gene as a cause of ultrarapid metabolism. There are pronounced interethnic differences in these allelic variants. When nortriptyline was given as single doses to healthy subjects, there was a close relationship between the rate of 10-hydroxylation and the number of functional CYP2D6 genes. Most neuroleptic drugs are also metabolized by CYP2D6. Exceptions are the atypical neuroleptics clozapine and olanzapine, which are mainly metabolized by CYP1A2. When haloperidol was given as a single oral dose to a panel of healthy Swedish Caucasians, PM of debrisoquine eliminated the drug slower than EM (PM=poor, EM=extensive metabolisers). Among eight patients treated with i.m. injection of haloperidol decanoate every 4 weeks, one patient having the genotype CYP2D6*4/*4 and thus a PM, had the highest plasma concentration of haloperidol, highest dopamine D2-receptor occupancy and most pronounced extrapyramidal side-effects. In Japan, plasma concentrations of haloperidol per dose unit have been shown to be related to the CYP2D6*10 allele. In Koreans, this relationship was confirmed at doses of haloperidol below 20 mg per day, but not at higher doses. These and other studies taken together show that at low doses haloperidol is metabolized by CYP2D6, while at high doses, this enzyme is saturated and then enzymes with a higher capacity, e.g. CYP3A4, are taking over. CYP2D6 catalyzes the metabolism of a large number of psychotropic drugs and the pronounced variation in its activity between individuals and populations contributes to the variation in treatment response and side effects. Also, it must be emphasized that when two drugs, both of which are substrates of CYP2D6, are co-administrated they may increase each others' plasma concentrations and potentiate therapeutic effects and adverse drug reactions.