Amisulpride doses and plasma levels in different age groups of patients with schizophrenia or schizoaffective disorder.

Because of a unique pharmacodynamic profile, amisulpride seems appropriate for treatment of elderly patients with schizophrenia. In a large-scale naturalistic therapeutic drug monitoring study, daily amisulpride dose, trough and dose-corrected amisulpride plasma levels, co-medication, clinical effectiveness (CGI) and side effects (UKU) were compared between age groups in 395 patients with schizophrenia or schizoaffective disorder (46% women; mean age 39.1 +/- 14.2 years, range 18-83 years) under amisulpride therapy. Mean amisulpride doses (574 +/- 269 mg/day), plasma levels (304 +/- 274 ng/mL), dose-corrected amisulpride plasma levels (C/D ratios, 0.52 +/- 0.41 ng/mL:mg), clinical response (at least moderate improvement, 71.6%), and side effects (any side effect, 32.2%; extrapyramidal symptoms, 14.9%) were comparable between age groups (P > 0.25). At higher age, significantly more benzodiazepines (P = 0.04), non-benzodiazepine hypnotics (P = 0.004) and non-psychotropic medications (P < 0.0001) were prescribed. The naturalistic study showed higher C/D ratios in women (P = 0.019) and a slight increase of C/D ratios with age (P = 0.026), but no substantial age-dependent effects on amisulpride doses or plasma levels. In patients above 60 years, clinical response was associated with lower amisulpride plasma levels (P = 0.016) at comparable doses. Neither the age-dependent decrease of amisulpride clearance nor the significantly higher prevalence of co-morbidity and co-medication seem to be the reasons for definite clinical concerns against amisulpride treatment of elderly if contraindications are seriously taken.

Reboxetine and cytochrome P450--comparison with paroxetine treatment in humans.

OBJECTIVES: The noradrenaline-selective antidepressant reboxetine in vitro is a weak inhibitor of both cytochrome P450 (CYP) 2D6 and CYP3A4. Thus, in this study the pharmacokinetics of reboxetine in relation to pharmacogenetics and the effects of reboxetine compared to paroxetine treatment on the CYP2D6 and CYP3A4 phenotype were analyzed in healthy control subjects. METHODS: Healthy male volunteers were treated with either 6 mg reboxetine (n = 26) or 30 mg paroxetine (n = 25). On Days 10/11 of treatment, serum concentrations of the antidepressants were measured and pharmacokinetic parameters calculated. Volunteers were phenotyped at the end of treatment and after at least 3 weeks washout (true phenotype) using 30 mg dextromethorphan (DM) hydrobromide given orally and measuring DM and metabolites in serum 2 h after intake. CYP2D6 and CYP2C19 genotypes were determined in parallel. RESULTS AND CONCLUSION: Reboxetine serum concentrations showed no correlation with the CYP2D6 genotype and the CYP2D6 phenotype, whereas paroxetine concentrations showed some dependence on CYP2D6. In contrast to in vitro investigations, indicating a major role of CYP3A4 in reboxetine metabolism, reboxetine concentrations in serum showed no correlation with the respective DM metabolic ratios. There was also no correlation between paroxetine concentrations and the CYP3A4 phenotype data. The CYP2C19 genotype (only heterozygosity) had no influence on reboxetine and paroxetine pharmacokinetics. There were only minor changes in the DM metabolite pattern on treatment with reboxetine and no evidence of enzyme inhibition was obtained. In contrast and as expected, paroxetine strongly inhibited CYP2D6. Thus, reboxetine treatment has no effect on the CYP2D6 genotype and no clinically relevant drug interactions involving CYP2D6 are anticipated.

Pharmacokinetics of selective serotonin reuptake inhibitors.

The five selective serotonin reuptake inhibitors (SSRIs), fluoxetine, fluvoxamine, paroxetine, sertraline, and citalopram, have similar antidepressant efficacy and a similar side effect profile. They differ, however, in their pharmacokinetic properties. Under steady-state concentrations, their half-lives range between 1 and 4 days for fluoxetine (7 and 15 days for norfluoxetine) and between 21 (paroxetine) and 36 (citalopram) hr for the other SSRIs. Sertraline and citalopram show linear and fluoxetine, fluvoxamine, and paroxetine nonlinear pharmacokinetics. SSRIs underlie an extensive metabolism with high interindividual variability, whereby cytochrome P450 (CYP) isoenzymes play a major role. Therefore, resulting blood concentrations are highly variable between individuals. Except for N-demethylated fluoxetine, metabolites of SSRIs do not contribute to clinical actions. Therapeutically effective blood concentrations are unclear so far, although there is evidence for minimal effective and upper-threshold concentrations that should not be exceeded. Paroxetine and, to a lesser degree, fluoxetine and norfluoxetine are potent inhibitors of CYP2D6 and fluvoxamine of CYP1A2 and CYP2C19. This can give rise to drug-drug interactions that may have no effect, lead to intoxication, or improve the therapeutic response. These different pharmacokinetic properties of the five SSRIs, especially their drug-drug interaction potential, should be considered when selecting a distinct SSRI for treatment of depression or other disorders with a suggested dysfunction of the serotonergic system in the brain.

CYP2D6 genotype and phenotyping by determination of dextromethorphan and metabolites in serum of healthy controls and of patients under psychotropic medication.

Fourteen drug free healthy volunteers and 22 psychiatric patients under psychotropic medication were phenotyped for their individual CYP2D6 activity using dextromethorphan as a probe drug. A solution containing 20 mg dextromethorphan was administered and blood was taken 60 min later for determination of dextromethorphan and metabolites in serum. For comparison, urine was collected over 8 h after ingestion of 20 mg dextromethorphan in a separate test. The CYP2D6 phenotype was determined from the ratio of dextromethorphan to dextrorphan. For genotyping, mutant alleles of the CYP2D6 gene were identified using allele-specific polymerase chain reactions. Genotyping revealed five poor metabolizers of CYP2D6. The others were extensive metabolizers. The ratio of dextromethorphan to dextrorphan ranged from 0.01-2.53 in serum and from 0.0007-4.252 in urine. Probit analysis of serum ratios revealed a bimodal distribution with an antimode at 0.126. According to this antimode, control subjects exhibited identical phenotypes and genotypes, whereas patients under paroxetine, moclobemide or metoprolol who had been genotyped as extensive metabolizers were poor metabolizer phenotypes. Administration of tricyclic antidepressants did not change the CYP2D6 phenotype. The serum assay was more rapid and more accurate than the standard urine approach. Therefore the determination of dextromethorphan and metabolites in serum could be advantageous to measure individual CYP2D6 activities in vivo and thus optimize the dosing of drugs metabolized by CYP2D6.

Increased bioavailability of oral melatonin after fluvoxamine coadministration.

BACKGROUND: Fluvoxamine, a selective serotonin reuptake inhibitor, is known to elevate melatonin serum concentrations. It has not been clear whether these effects might be attributed to an increased melatonin production or to an decreased elimination of melatonin. The latter hypothesis was tested by this study. METHODS: Five healthy male volunteers (one CYP2D6 poor metabolizer) received 5 mg melatonin either with or without coadministration of 50 mg fluvoxamine. Serum concentrations of melatonin and fluvoxamine were assessed from 0 to 28 hours after melatonin intake. RESULTS: Coadministration of fluvoxamine, on average, led to an 17-fold higher (P < .05) area under concentration-time curve (AUC) and a 12-fold higher (P < .01) serum peak concentration (Cmax) of melatonin. The terminal elimination half-life was not significantly affected. The AUC and Cmax of fluvoxamine were about three times higher and the half-life was about two times higher in the poor metabolizer. There was a correlation (r = 0.63; P < .01) between the melatonin and fluvoxamine serum concentrations. The poor metabolizer was found to have a more pronounced and longer-lasting effect of fluvoxamine on the pharmacokinetics of melatonin. CONCLUSION: This study showed an increase in the bioavailability of oral melatonin by coadministration of fluvoxamine. The effects of fluvoxamine on the melatonin serum concentrations in patients with depression might therefore be caused by inhibition of the elimination of melatonin and not attributable to an increased production of melatonin.

Inhibition of cytochrome P4502D6 activity with paroxetine normalizes the ultrarapid metabolizer phenotype as measured by nortriptyline pharmacokinetics and the debrisoquin test.

BACKGROUND: The ultrarapid metabolizer phenotype of the cytochrome P4502D6 (CYP2D6) enzyme has been considered a relevant cause of nonresponse to antidepressant drug therapy. Prescribing high doses of antidepressants to such patients leads to high concentrations of potentially toxic metabolites and an increased risk for adverse reactions. Normalization of the metabolic status of ultrarapid metabolizers by inhibition of CYP2D6 activity could offer a clinically acceptable method to successfully treat such patients with antidepressants. METHODS: Five ultrarapid metabolizers with a CYP2D6 gene duplication or triplication were treated with 25 mg nortriptyline twice a day for 3 consecutive weeks, alone during the first week and concomitantly with the CYP2D6 inhibitor paroxetine 10 mg or 20 mg twice a day, respectively, during the second and third weeks. After the third week, nortriptyline was discontinued and the subjects were treated with paroxetine 20 mg twice a day during the fourth study week. At the end of each study week, the steady-state pharmacokinetic parameters of nortriptyline or paroxetine were determined within the dose interval. In addition, the CYP2D6 phenotype was determined by debrisoquin (INN, debrisoquine) test at baseline and at the end of each study phase. Treatment-related adverse events were recorded during drug administration and for 1 week thereafter. RESULTS: All 5 subjects had very low (subtherapeutic) nortriptyline concentrations after 7 days' treatment with nortriptyline only. Addition of paroxetine 10 mg twice a day to the nortriptyline regimen resulted in a change in all individuals to the "normal" extensive debrisoquine metabolizer phenotype, and therapeutic plasma nortriptyline concentrations were achieved in 4 of 5 subjects after a 3 times mean increase in nortriptyline trough concentration (P =.0011). Doubling the paroxetine dose caused a 15 times mean increase in paroxetine trough concentration (P <.001), indicating strong inhibition by paroxetine of its own metabolism. The high paroxetine concentrations in 2 subjects caused them to have the poor debrisoquine metabolizer phenotype and resulted in a further increase in plasma nortriptyline trough concentration (P =.0099). A strong correlation (rank correlation coefficient [r(s)] = 0.89; P <.0001) was observed between paroxetine and nortriptyline trough concentrations. Paroxetine also significantly decreased the fluctuation of nortriptyline concentrations within the dose interval. One subject discontinued the study after the second study week because of adverse effects; otherwise, the study drugs were well tolerated. CONCLUSIONS: Paroxetine, with a daily dosage from 20 to 40 mg, is an effective tool in normalizing the metabolic status of CYP2D6 ultrarapid metabolizers.

Orally given melatonin may serve as a probe drug for cytochrome P450 1A2 activity in vivo: a pilot study.

BACKGROUND: Melatonin is a hormone that is metabolized by cytochrome P450 (CYP) 1A2 to its main primary metabolite 6-hydroxymelatonin. We therefore evaluated the utility of oral melatonin as a marker of hepatic CYP1A2 activity. METHODS: Twenty-five milligrams of melatonin was given at 9:30 am to 12 healthy Swedish volunteers, who had previously been phenotyped for CYP1A2 with caffeine. Melatonin and conjugated 6-hydroxymelatonin were analyzed by liquid chromatography-mass spectrometry in blood samples taken between 0.5 and 6.5 hours after drug intake. Serum concentrations of melatonin and conjugated 6-hydroxymelatonin, or their ratio at different time points, and the apparent melatonin clearance were tested for correlation with caffeine clearance. RESULTS: We found a significant correlation between apparent clearance of melatonin and caffeine clearance with a Spearman rank correlation coefficient (Rs) of 0.75 (P =.005). The melatonin concentration 1.5 hours after administration also closely correlated with the caffeine clearance (Rs = -0.62; P =.03). Inclusion of conjugated 6-hydroxymelatonin gave no closer correlations. CONCLUSION: Melatonin might be developed as an alternative to caffeine as a probe drug for CYP1A2 phenotyping.

Combination treatment with clomipramine and fluvoxamine: drug monitoring, safety, and tolerability data.

BACKGROUND: Combination treatment with tricyclic antidepressants (TCAs) and serotonin selective reuptake inhibitors (SSRIs) is an increasingly employed strategy especially in depressed patients unresponsive to monotherapy. Comedications with SSRIs, however, may be hazardous owing to pharmacokinetic interactions that can result in elevated serum TCA levels. For the combinations, safety and tolerability data are lacking. METHOD: We report tolerability and safety of combined treatment with fluvoxamine and clomipramine (CMI) in 22 patients. Most patients suffered from depression and obsessive-compulsive symptoms. Diagnoses were made according to DSM-III-R criteria. Serum levels of CMI, N-desmethylclomipramine (DCMI), and 8-hydroxylated metabolites were determined. EEG, ECG, and laboratory parameters and adverse effects reported by the patients, as well as global clinical improvement, were assessed. RESULTS: Generally, fluvoxamine/clomipramine comedication was well tolerated. Serum CMI levels reached 500 to 1200 ng/mL in half of the patients, while corresponding levels for DCMI and 8-hydroxylated metabolites were low. Moreover, the ratios of N-demethylation DCMI:CMI calculated from the ratios of drug concentrations in serum were markedly lower under comedication than under CMI monotherapy. Alterations in EEG, ECG, and laboratory parameters that had clinical relevance were rarely observed and were reversible after dose reduction of CMI. However, 2 patients developed myoclonic jerks. A majority of patients improved clinically during combination treatment. Clinically relevant side effects were absent in patients with serum CMI and DCMI levels below 450 ng/mL and ratios of N-demethylation below 0.3. CONCLUSION: Our results suggest that comedication of fluvoxamine and clomipramine will result in markedly elevated serum clomipramine levels. Therefore, combination treatment with fluvoxamine and clomipramine should be carefully monitored by determination of serum levels of the TCA. Clinically, the pharmacokinetic interactions between fluvoxamine and clomipramine may be well tolerated in a majority of patients. However, in a few patients, higher serum levels may be associated with an increased risk of EEG changes and changes of intracardiac conductance. EEG and ECG should be used regularly to monitor comedicated patients.

Inhibition of antidepressant demethylation and hydroxylation by fluvoxamine in depressed patients.

Bidirectional drug interactions between fluvoxamine and classical antidepressants were studied in depressed patients. A column switching technique combined with high performance liquid chromatography (HPLC) enabled automated analyses of plasma for simultaneous determination of fluvoxamine, tricyclic and tetracyclic antidepressants and demethylated and major hydroxylated metabolites in a single HPLC run. The measurements revealed that fluvoxamine inhibited N-demethylation of imipramine, clomipramine, amitriptyline and maprotiline whereas interferences with hydroxylation reactions were restricted to aromatic 8-hydroxylation of clomipramine. In patients under fluvoxamine monotherapy before comedication, plasma concentrations of fluvoxamine increased after administration of a tricyclic antidepressant, thus indicating bidirectional drug interactions. The inhibitory effects of fluvoxamine on the metabolism of classical antidepressants disappeared after discontinuation of concomitant fluvoxamine treatment within at least 1-2 weeks. The reported alterations in drug metabolism observed in depressed patients who were under fluvoxamine/tricyclic antidepressant comedication suggested that careful supervision and regular drug monitoring are necessary in such patients.

Non-competitive inhibition of clomipramine N-demethylation by fluvoxamine.

The selective serotonin reuptake inhibitor fluvoxamine interferes with the metabolism of tricyclic antidepressants. The present investigation was set out to characterize these interactions in vitro using rat liver microsomes and in vivo by analysing levels of clomipramine and metabolites in sera of depressed patients treated concomitantly with fluvoxamine and clomipramine. Clomipramine was N-demethylated and hydroxylated in vitro by microsomes to N-desmethyl-clomipramine, 8-hydroxyclomipramine, and 10-hydroxyclomipramine. Kinetic analyses revealed Km values of 6.2 microM for N-demethylation and 1.2 microM for 8-hydroxylation. Fluvoxamine was a non-competitive inhibitor for N-demethylation with mean Ki value of 6 microM. In the sera of patients treated with daily doses of 150 mg clomipramine and varying doses of fluvoxamine, decrease in the formation of N-desmethylclomipramine and 8-hydroxyclomipramine were found in comparison to those in sera of patients receiving clomipramine as monotherapy. Taken together, the data give evidence that fluvoxamine is a potent non-competitive inhibitor of N-demethylation and to a minor extent of 8-hydroxylation of clomipramine. Because of the species differences in the metabolism of xenobiotics between rodents and humans, conclusions from animal studies on the clinical situation must be drawn cautiously. Nevertheless, the in vitro approach was helpful to understand drug interactions between clomipramine and fluvoxamine in psychiatric patients.

Doxepin and its metabolites in plasma and cerebrospinal fluid in depressed patients.

Little information exists on the concentrations of antidepressants and their metabolites in CSF. We measured plasma and CSF levels of trans-doxepin (trans-DOX) and DOX metabolites in 12 depressed patients treated with DOX (250 mg/day) for 6 days. Spinal taps and blood samples were taken on day 7, 10 h after drug administration. Trans-DOX, cis-desmethyldoxepin (cis-DM-DOX), trans-desmethyldoxepin (trans-DM-DOX) and di-desmethyldoxepin (DDM-DOX) were analyzed in CSF and plasma samples by HPLC with column-switching. Although DOX was given as a mixture of 85% trans-DOX and 15% of the pharmacologically more active cis-DOX, we found similar amounts of cis-DM-DOX and trans-DM-DOX in plasma (59.8 +/- 45.1 versus 72.0 +/- 60.0 ng/ml; NS), suggesting that isomerization of DOX had taken place. Trans-DOX and DOX metabolites could be detected in CSF of most patients. Relatively low CSF concentrations of the active metabolite cis-DM-DOX were measured. Clinical efficacy, as assessed by HAMD scores, was not significantly related to plasma or CSF concentrations of trans-DOX or its metabolites. Trans-DOX and DOX metabolites were distributed differently between plasma and CSF. It is concluded that isomerization of DOX is not only relevant for neuronal uptake inhibition, but also for the transport of the metabolites.

Inhibition of dextromethorphan metabolism by moclobemide.

This pilot study was conducted to evaluate the potential of the new antidepressant moclobemide to inhibit the cytochrome enzyme P4502D6 (CYP2D6) using the cough suppressant dextromethorphan as a substrate in four extensive metabolizers (EM) of debrisoquine. The subjects received seven oral doses of 20 mg dextromethorphan at 4-h intervals over 2 days (1 and 2) and subsequently moclobemide (300 mg b.i.d.) for 9 days. On days 10 and 11, they received seven doses of 20 mg dextromethorphan in addition to moclobemide. During monotreatment and combined treatment, blood was collected on days 2 and 11, respectively, for determination of dextromethorphan and its demethylated metabolites using automated high-performance liquid chromatography with column switching. Concurrent administration of moclobemide markedly reduced the O-demethylation of dextromethorphan, whereas the N-demethylation of dextrorphan to hydroxymorphinan was not affected. The findings indicate that moclobemide can affect the pharmacokinetics of drugs that are mainly metabolized by CYP2D6.

Steady state concentrations of clomipramine and its major metabolite desmethylclomipramine in rat brain and serum after oral administration of clomipramine.

Twenty male Sprague-Dawley rats received five oral doses of clomipramine 20 mg/kg at 4-h intervals. The animals were decapitated 1, 2, 3, 5 and 12 h after the last dose for determination of clomipramine and desmethylclomipramine in serum and frontal cerebral cortex. Time dependent concentrations of clomipramine and desmethylclomipramine paralleled in serum and brain. Half-lives were similar in serum and brain with 7.8 versus 6.2 h and 5.5 versus 5.0 h for clomipramine and desmethylclomipramine, respectively. Absolute concentrations, however, were markedly higher in brain than in serum - 12.5 fold for clomipramine and 7.4 fold for desmethylclomipramine. The data indicate that serum and brain concentrations of clomipramine and its demethylated metabolite are rapidly exchanged between blood and brain. Assuming that blood and brain kinetics in man and rat are comparable, it is concluded that monitoring blood concentrations of clomipramine and desmethylclomipramine is a useful way to evaluate brain concentrations.

The role of cytochrome P450 2D6 in the metabolism of moclobemide.

The metabolic fate of moclobemide (Ro 11-1163), a new reversible and selective inhibitor of monoamine oxidase type A (MAO-A), has been assessed in a pilot study in 2 debrisoquine poor metabolizers (PM) and 4 extensive metabolizers (EM) after multiple oral dosings of moclobemide with and without co-medication of dextromethorphan. Absorption and disposition parameters were not different between PM and EM. Concurrent application of dextromethorphan, a selective substrate of CYP2D6, did not affect the pharmacokinetics of moclobemide. These results indicate that the cytochromal isoenzyme CYP2D6 does not play a major role in the metabolic degradation of moclobemide. Limited CYP2D6 activities because of a genetic defect or co-medications with CYP2D6 substrates should therefore not give rise to elevated moclobemide blood levels.

Distribution of clozapine and desmethylclozapine between blood and brain in rats.

Desmethylclozapine is the major metabolite of clozapine in serum. Although the metabolite is pharmacologically active in vitro, the occurrence of desmethylclozapine in brain under steady-state conditions and its role for clinical actions of clozapine are unclear. In this study 20 male Sprague-Dawley rats received five oral doses of clozapine 20 mg/kg at 1.5-h intervals. At 0.5, 1, 2 and 5 h after the last administration, at a time four animals were killed for analysis of clozapine and desmethylclozapine concentrations in serum and brain. The treatment yielded steady-state serum concentrations of clozapine that are considered as therapeutically effective in man. Desmethylclozapine concentrations exceeded those of clozapine at 2-5 h after drug application. In brain, drug concentrations were 15.8-fold higher for clozapine than in serum, but only 2.7-fold higher for desmethylclozapine. The brain clozapine concentrations exceeded those of desmethylclozapine by about 3 times. These data indicate that desmethylclozapine is unlikely to play a role for CNS-mediated effects.

Interaction of modafinil and clomipramine as comedication in a narcoleptic patient.

Modafinil is a psychostimulant compound that is just now becoming available in many countries for treatment of narcoleptic and hypersomnic patients. Whereas sleep attacks and drowsiness can be effectively improved, the drug does not sufficiently reduce cataplectic seizures. It therefore is often used in combination with tricyclic antidepressant medication, although little is known about the possible interactions. This case report describes a narcoleptic patient chronically treated with clomipramine who started receiving modafinil. The blood concentrations of clomipramine and its metabolite showed a significant dose-dependent and reversible increase under modafinil. Since the patient was genotypically and phenotypically a cytochrome P450 2D6 poor metabolizer, the authors attribute the relevant pharmacokinetic interaction to another clomipramine-metabolizing enzyme.

Gender aspects in the clinical treatment of schizophrenic inpatients with amisulpride: a therapeutic drug monitoring study.

INTRODUCTION: It is assumed that female and male schizophrenic patients respond differentially to acute and chronic treatment with antipsychotics because of pharmacokinetic and pharmacodynamic factors linked to hormonal and constitutional gender differences. However, to date no empirical evidence exists in support of this notion. METHODS: In a naturalistic clinical study, we investigated gender differences in a sample of schizophrenic inpatients with acute exacerbation treated with the atypical antipsychotic amisulpride, a selective dopamine D2/D3 receptor antagonist with proven antipsychotic efficacy. Prescribed amisulpride dose, plasma level, clinical response (CGI), and side effects (UKU) were assessed in 99 patients (62 % male, age 18-66 years) under antipsychotic monotherapy with amisulpride at daily doses > or = 400 mg. RESULTS: Female patients were significantly older (38.5 +/- 11.8 years) than male patients (32.3 +/- 10.9 years; P = 0.01). Prescribed amisulpride doses were comparable for men (673 +/- 216 mg) and women (665 +/- 229 mg). However, dose-corrected steady-state amisulpride plasma levels (men 0.41 +/- 0.31 ng/mL/mg; women 0.60 +/- 0.39 ng/mL/mg; P = 0.007) were significantly higher in female patients even after age adjustment. No significant differences between men and women emerged with respect to clinical response (77 % vs. 79 %, respectively) and the occurrence of any side effect (41 % vs. 37 %, respectively). DISCUSSION: Except for higher dose-related plasma amisulpride levels in women, the explorative study unveiled no clinically relevant gender-specific aspects regarding prescribed dose, effectiveness, and side effects.

CYP2D6 polymorphism and clinical effect of the antidepressant venlafaxine.

BACKGROUND: Venlafaxine (V) is a mixed serotonin and noradrenaline reuptake inhibitor used as a first-line treatment of depressive disorders. It is metabolized primarily by the highly polymorphic cytochrome P450 (CYP) enzyme CYP2D6 to yield a pharmacologically active metabolite, O-desmethylvenlafaxine (ODV), and to a lesser extent by CYP3A4, to yield N-desmethylvenlafaxine (NDV). OBJECTIVES: The aim of this study was to assess whether the O-demethylation phenotype of V has an impact on the pharmacokinetics and clinical outcome. METHOD: In 100 patients treated with V, serum concentrations of V, ODV and NDV and the ratios of concentrations ODV/V as a measure of O-demethylation were determined. Individuals exhibiting abnormally high or low metabolic ratios of ODV/V were selected for genotyping. Clinical effects were monitored by the Clinical Global Impressions Scale and side effects by the UKU (Udvalg for Kliniske Undersogelser Side Effect Rating Scale) rating scale. RESULTS: There was wide inter-individual variability in ODV/V ratios. The median ratio ODV/V was 1.8 and the 10th and 90th percentiles 0.3 and 5.2, respectively. Individuals with ODV/V ratios below 0.3 were all identified as poor metabolizers (PM), with the genotypes *6/*4 (n = 1), *5/*4 (n = 2) or *6/*6 (n = 1). Individuals with ratios above 5.2 were all ultra rapid metabolizers (UM, n = 6) due to gene duplications. Five individuals with intermediate metabolic activity (ODV/V, 1.1 +/- 0.8) were heterozygotes with the CYP2D6*4 genotype, and one patient with an intermediate metabolic ratio of 4.8 had the genotype *4/2x*1. Clinical outcome measurements revealed that patients with ODV/V ratios below 0.3 had more side effects (P < 0.005) and reduced serum concentrations of sodium (P < 0.05) in comparison with other patients. Gastrointestinal side effects, notably nausea, vomiting and diarrhoea were the most common. Differences in therapeutic efficacy were not significant between the different phenotypes. CONCLUSION: The O-demethylation phenotype of V depends strongly on the CYP2D6 genotype. A PM phenotype of CYP2D6 increases the risk of side effects.

Region specific distribution of levomepromazine in the human brain.

OBJECTIVE: The aim of this study was to examine concentrations of levomepromazine and its metabolite desmethyl-levomepromazine in different regions of human brain and in relationship to drug-free time. METHODS: Drug concentrations were measured in up to 43 regions of 5 postmortem human brains of patients previously treated with levomepromazine. To enable statistical comparison across brain regions several smaller brain areas were put together to form larger brain areas (cortex cerebri, limbic system, cerebellum, basal ganglia, thalamus). Mean values of drug concentrations in these larger brain areas were used in a repeated measurement ANOVA to analyze for region specific distribution. The elimination half-life in brain tissue was estimated with a NONMEM population kinetic analysis using the mean value of all brain regions of an individual case. RESULTS: Levomepromazine and desmethyl-levomepromazine appear to accumulate in human brain tissue relative to blood. Mean concentrations differed largely between individual brains, in part due to differences in dose of drug, duration of treatment and drug-free time before death. There was an apparent region-specific difference in levomepromazine concentrations with highest values in the basal ganglia (mean 316 ng/g) and lowest values in the cortex cerebri (mean 209 ng/g). The elimination half-life from brain tissue is longer than from blood and was calculated to be about one week. Similar results were obtained with desmethyl-levomepromazine. CONCLUSIONS: Levomepromazine shows a region-specific distribution in the human brain with highest values in the basal ganglia. This might be the consequence of low expression of the metabolic enzyme Cyp2D6 in the basal ganglia. If this finding is true also for other neuroleptic drugs it might increase our understanding of preferential toxicity of neuroleptic drugs against basal ganglia structures and higher volumes of basal ganglia of neuroleptic-treated patients. Furthermore, patients exposed to levomepromazine cannot be considered to be free of residual effects of the drug for a number of weeks after withdrawal.