Plasma Concentrations Of Quetiapine Research Articles

Post-therapy plasma concentrations of quetiapine in Taiwanese patients.

Quetiapine is widely used to treat psychiatric disorders such as major depression, generalized anxiety disorder, dysthymic disorder, and insomnia other than schizophrenia and bipolar disorder. This study investigated the diagnostic distribution of quetiapine use in patients in a psychiatric hospital, the doses of quetiapine prescribed, and the plasma concentrations (Cps) of quetiapine and active metabolites. We enrolled 107 patients who had been prescribed quetiapine for at least 4 weeks. Diagnoses, demographics, and concomitant medications were recorded. Blood sampling was performed in the morning, approximately 12h after the before-bed dose of quetiapine. Diagnoses comprised schizophrenia (n=25), bipolar disorder (n=51), major depression (n=15), dysthymic disorder (n=9), and others (n=7). The daily dose (DD) of quetiapine ranged from 25 to 800 (175.9 ± 184.4)mg, with the mean Cp being 105.6 ± 215.3ng/ml, with a mean Cps/DD ratio of 0.58 ± 0.55 ng/ml/mg. There was a moderate positive linear correlation between the dose and Cps of quetiapine (r=0.60), and the interpatient variation in Cps/DD ratio was up to 26-fold. Quetiapine is used in various doses to treat many psychiatric disorders other than psychosis, and it is usually prescribed as a secondary antipsychotic for symptoms such as insomnia or agitation. A wide interpatient variation of the Cps/DD ratio was noticed. Patients of East Asian descent may exhibit a 50% to 100% increase in the Cps/DD ratio for quetiapine compared with patients of Western descent.

Dose Adjustment of Quetiapine and Aripiprazole for Pregnant Women Using Physiologically Based Pharmacokinetic Modeling and Simulation.

Quetiapine and aripiprazole are currently prescribed for pregnant women to treat schizophrenia and bipolar disorder. A dramlatic decline in the plasma concentrations of these two drugs was observed if the doses remained fixed throughout pregnancy. This study aims to develop physiologically based pharmacokinetic(PBPK) models to predict the pharmacokinetics of quetiapine, aripiprazole, and the active aripiprazole metabolite dehydroaripiprazole during pregnancy. We developed models using a combined 'bottom-up' and 'top-down' strategy. Models were verified by assessing goodness-of-fit plots and ratios of predicted-to-observed pharmacokinetic parameters. To extrapolate to pregnancy, we considered anatomical, physiological, and metabolic alterations. The in silico models were applied to predict steady-state pharmacokinetics in the three stages of pregnancy and to inform dose selection. We successfully constructed PBPK models that accurately predicted the pharmacokinetics of drugs in the adult population. Predictions suggested that the area under the concentration-time curve at steady state in the first, second, and third trimesters, respectively, decreased by 8.7%, 35.0%, and 49.1% for quetiapine and 12.6%, 38.8%, and 60.9% for the active moiety of aripiprazole. The third-trimester plasma concentrations of quetiapine were below the lower limit of the therapeutic range (100 ng/mL) for most of the time interval, and aripiprazole was entirely unable to reach its effective concentration (150 ng/mL). According to PBPK predictions, the doses should be increased in the latter two trimesters. We generally recommend that women during late pregnancy take at least 2.5- and 2-times their baseline doses of quetiapine and aripiprazole, respectively.

Effect of N-Desalkylquetiapine/Quetiapine Plasma Level Ratio on Anxiety and Depression in Bipolar Disorder: A Prospective Observational Study.

The aim of this study was to analyze the relationships between quetiapine and N-desalkylquetiapine plasma levels and clinical improvement, particularly, in regard to depressive and anxious symptoms and to hostility. This was a prospective observational study that involved 37 outpatients diagnosed as having bipolar disorder I or II. All the patients were observed during a clinical acute and postacute phase. Patients were prescribed 50-800 mg of quetiapine. Patients were evaluated at baseline, after 15 days and after 3 months using the Brief Psychiatry Rating Scale with particular reference to the dimensions of depression, anxiety, and hostility. The plasma concentrations of quetiapine and N-desalkylquetiapine were determined after 3 months using blood samples taken at steady state. There was a significant relationship between the N-desalkylquetiapine/quetiapine ratio and the improvement in the depression dimension, and there was not a significant relationship between the N-desalkylquetiapine/quetiapine ratio and anxiety and hostility improvement. Quetiapine treatment was well tolerated, and there were no extrapyramidal, anticholinergic, or other side effects to note. There was no relationship between plasma quetiapine or N-desalkylquetiapine concentrations and side effects. Our findings confirm the efficacy of quetiapine on depressive symptoms, and the available data support that quetiapine's antidepressant activity is mediated by the active metabolite norquetiapine, and it exemplifies the case of an active metabolite that can make a drug like quetiapine originally introduced as an antipsychotic a useful antidepressant agent.

Effects of green tea extracts on the pharmacokinetics of quetiapine in rats.

Quetiapine is an atypical antipsychotic, used clinically in the treatment of schizophrenia, acute mania in bipolar disorders, and bipolar depression in adults. In this study, the effect of green tea extracts (GTE) on the pharmacokinetics of quetiapine (substrate of CYP3A4) was investigated in rats. Male Wistar albino rats received GTE (175 mg/kg) or saline (control) by oral gavage for 7 days before a single intragastric administration of 25 mg/kg quetiapine. Plasma concentrations of quetiapine were measured up to 12 h after its administration by a validated ultraperformance liquid chromatography-tandem mass spectroscopy. Pretreatment with GTE produced significant reductions in the maximum plasma concentration and area under the curve of quetiapine by 45% and 35%, respectively, compared to quetiapine alone. However, GTE did not produce significant change in elimination half-life and oral clearance of quetiapine. This study concluded that GTE may decrease the bioavailability of quetiapine when coadministered.

Influence of ABCB1 and CYP3A5 genetic polymorphisms on the pharmacokinetics of quetiapine in healthy volunteers

Quetiapine is an atypical antipsychotic drug used to treat schizophrenia and acute episodes of mania. Quetiapine is metabolized by CYP3A enzymes including CYP3A5 and is a substrate of P-glycoprotein, an efflux drug transporter encoded by the ABCB1 gene. We assessed the effects of ABCB1 [c.1236C>T (rs1128503), c.2677G>T/A (rs2032582), c.3435C>T (rs1045642)] and CYP3A5*3 (6986A>G) (rs776746) polymorphisms on the pharmacokinetics of quetiapine in humans. Forty healthy male individuals were enrolled, and their ABCB1 and CYP3A5 polymorphisms were assessed. After a single dose of 100 mg quetiapine was administered, plasma concentrations of quetiapine were measured for 24 h and pharmacokinetic analysis was carried out. The ABCB1 polymorphisms including c.1236C>T, c.2677G>T/A, and c.3435C>>T did not affect plasma levels of quetiapine, and its pharmacokinetic parameters did not differ among ABCB1 genotype groups. However, the CYP3A5*3 polymorphism significantly affected the plasma level of quetiapine and its pharmacokinetics. The peak plasma concentration of quetiapine was 208.39 ng/ml for CYP3A5*1/*1, 243.46 ng/ml for CYP3A5*1/*3, and 332.94 ng/ml for CYP3A5*3/*3 (P=0.0118). The mean AUC(inf) (area under the time vs. concentration curve from 0 to infinity) value was 627.3, 712.77, and 1045.29 ng h/ml, respectively (P=0.0017). The results indicated that the genetic polymorphism of CYP3A5*3 but not ABCB1 significantly influences the plasma level of quetiapine and its pharmacokinetics. These findings suggest that the CYP3A5 genetic polymorphism affects the disposition of quetiapine and provide a plausible explanation for interindividual variation in the disposition of this drug.

Norepinephrine transporter occupancy in the human brain after oral administration of quetiapine XR

Quetiapine, originally developed as an antipsychotic, demonstrates efficacy in clinical studies of schizophrenia, bipolar mania and depression, major depressive disorder and generalized anxiety disorder. This broad spectrum of efficacy was not predicted from the preclinical pharmacology of quetiapine. Binding studies in vitro show that quetiapine and its major active human metabolite, norquetiapine, have moderate to high affinity for dopamine D2 and serotonin 5-HT2A receptors, while norquetiapine alone has high affinity for the norepinephrine transporter (NET). This positron emission tomography (PET) study measured NET occupancy in human subjects treated with extended-release quetiapine (quetiapine XR) at doses relevant in the treatment of depression. PET measurements using the specific NET radioligand (S,S)-[(18)F]FMeNER-D2 were performed before and after quetiapine XR treatment at 150 and 300 mg/d for 6-8 d in nine healthy males (aged 21-33 yr). Regions of interest were defined for the thalamus, using the caudate as reference region. NET occupancy was calculated using a target:reference region ratio method. Plasma concentrations of quetiapine and norquetiapine were monitored during PET measurements. Following quetiapine XR treatment, the mean NET occupancy in the thalamus was 19 and 35%, respectively, at quetiapine XR doses of 150 and 300 mg/d. The estimated plasma concentration of norquetiapine corresponding to 50% NET occupancy was 161 ng/ml. This is the first demonstration of NET occupancy by an antipsychotic in the human brain. NET inhibition is accepted as a mechanism of antidepressant activity. NET occupancy may therefore contribute to the broad spectrum of efficacy of quetiapine.

MDR-1 genotypes and quetiapine pharmacokinetics in healthy volunteers

P-glycoprotein is an efflux transporter encoded by the multidrug-resistance MDR-1 gene, which influences the absorption and excretion of a variety of drugs. The relation between quetiapine pharmacokinetics and MDR-1 genetic polymorphisms remains controversial. Therefore, the aim of the present study was to analyze the association between quetiapine plasma concentrations and MDR-1 genetic polymorphisms in a bioequivalence trial. Quetiapine bioequivalence was studied in 24 unrelated healthy Caucasian adults with an open-label, randomized, cross-over, two-sequence and two-period design. Subjects were genotyped for 3435C>T and 1236C>T single-nucleotide polymorphisms. A linear mixed model was performed to compare pharmacokinetic parameters. Subjects with 3435T/T genotype vs. C carriers showed a higher area under the concentration-time curve from 0 to 36 h (p=0.01). Subjects classified according to 1236C>T SNP and haplotypes showed no statistically significant differences. These results suggest that the polymorphic MDR-1, in particular the 3435C>T allelic variant, might influence plasma levels of quetiapine.

Plasma Concentrations of Quetiapine, N-Desalkylquetiapine, O-Desalkylquetiapine, 7-Hydroxyquetiapine, and Quetiapine Sulfoxide in Relation to Quetiapine Dose, Formulation, and Other Factors

N-Desalkylquetiapine may be a pharmacologically active quetiapine metabolite. However, information on plasma concentrations of N-desalkylquetiapine and other quetiapine metabolites attained during quetiapine therapy is scant. The aim of this study was to investigate plasma concentrations of quetiapine, N-desalkylquetiapine, O-desalkylquetiapine, 7-hydroxyquetiapine, and quetiapine sulfoxide attained during therapy and analyze the data with respect to prescribed dose and other variables. Quetiapine and its metabolites were measured in plasma samples submitted for quetiapine therapeutic drug monitoring (2009-2011). Concentration, metabolic ratio, and concentration corrected for dose (C/D) were investigated against quetiapine dose, age, sex, and formulation. Sample results were excluded if nonadherence with therapy was queried. There were 99 samples from 59 patients. N-Desalkylquetiapine plasma concentrations showed the strongest correlation with dose of all analytes, but O-desalkylquetiapine and quetiapine sulfoxide were strongly correlated to plasma quetiapine concentrations. There was no significant difference in C/D for any analyte between males and females and no correlation to age. Quetiapine and quetiapine sulfoxide C/D were significantly different (P < 0.01) between patients prescribed immediate- and extended-release formulations. Quetiapine, 7-hydroxyquetiapine and quetiapine sulfoxide C/D showed significant variation (P < 0.02) between those samples taken 10-14 hours postdose as compared with that of 16-24 hours postdose, but there was no significant effect as regards N-desalkylquetiapine. Plasma quetiapine, O-desalkylquetiapine, 7-hydroxyquetiapine, and quetiapine sulfoxide concentrations were significantly affected by formulation and/or time since last dose. Plasma N-desalkylquetiapine concentrations were not affected by either factor therefore may be a better marker for quetiapine exposure than plasma quetiapine concentrations.

Pharmacokinetics and Pharmacodynamics of Quetiapine in a Patient with a Massive Overdose

We present a case of massive overdose with the atypical antipsychotic quetiapine in a 34-year-old woman (body weight 65 kg). At admission, approximately 2 to 4 hours after ingestion of approximately 24 g of quetiapine, the patient was comatose (Glasgow Coma Scale score 5), requiring orotracheal intubation and transfer to the intensive care unit. Because of myoclonic jerks and generalized seizures, benzodiazepines were administered. In addition to transient mild hypotension after intubation, the main cardiovascular manifestation was sinus tachycardia. The QT interval was normal, and the QTc interval (Bazett's correction) was maximally prolonged to 620 ms. However, no malignant arrhythmias were observed. The patient recovered within 2 days but remained agitated and aggressive, for which she was transferred to the psychiatric clinic. The pharmacokinetics of quetiapine in such a large overdose could not be described by simple first-order kinetics. The initially observed rapid decline of the plasma concentrations of quetiapine could be simulated by first-order kinetics (half life = 4.1 hr) and can most probably be explained by rapid distribution into tissues. The final elimination of the drug from the body occurred after approximately 34 hours at much slower rate, most probably reflecting redistribution from tissues into blood and consecutive hepatic clearance of the drug.

Therapeutic Drug Monitoring of Quetiapine: Effect of Coadministration with Antiepileptic Drugs in Patients with Psychiatric Disorders

Antiepileptic agents, particularly those with mood-stabilizing properties, are increasingly used in the manage- ment of psychiatric disorders and may be prescribed in combination with antipsychotics. Aim of the present study was to evaluate the pharmacokinetic interaction between various antiepileptics and quetiapine, a second-generation antipsychotic, in psychiatric patients, by using data from a therapeutic drug monitoring service. Steady-state plasma concentrations of quetiapine were compared in patients treated with quetiapine alone (controls, n=35) and in patients comedicated with val- proic acid (n=19), lamotrigine (n=16), carbamazepine (n=6), topiramate (n=6) and oxcarbazepine (n=5). The six groups were matched for sex, age and daily dose of quetiapine. Dose-normalized plasma concentrations of quetiapine were sig- nificantly lower in the carbamazepine group than in the control group (p<0.001), while there were no differences in plasma quetiapine concentrations between the valproic acid, lamotrigine, topiramate or oxcarbazepine groups and the con- trol group. In 5 patients assessed on and off carbamazepine comedication, dose-normalized plasma concentrations of quetiapine were significantly lower during combination therapy than on quetiapine alone (p<0.01). By contrast, no appre- ciable changes in plasma levels of quetiapine were found in the 8 and 6 patients assessed on and off valproic acid or lamo- trigine comedication, respectively. These findings confirm that carbamazepine decreases markedly steady-state plasma concentrations of quetiapine, presumably by inducing its CYP3A4-mediated biotransformation. Conversely, concomitant administration of therapeutic doses of valproic acid, lamotrigine, topiramate or oxcarbazepine does not appear to affect significantly plasma levels of quetiapine.

Influence of age, gender, body weight and valproate comedication on quetiapine plasma concentrations

Quetiapine is a second-generation antipsychotic with a favourable risk/benefit profile that is increasingly used in psychiatric patients. Similar to other antipsychotics, the efficacy and adverse effects of quetiapine depend much more on the actual plasma concentration of the active drug than on the prescribed dose. The present study investigated whether age, gender, body weight or certain comedications influence quetiapine plasma concentration by determining quetiapine plasma levels by tandem mass spectrometry in 94 (36 male and 58 female) patients aged 42.2 +/- 20.0 years. Older age was a significant predictor of a higher quetiapine plasma concentration, with a mean increase of weight-corrected concentration/dose ratio of 11% per 10 years of age (P = 0.003). In females, the concentration/dose (C/D) ratio was 35.4% higher than in males (adjusted mean 0.144 ng/ml/mg for males versus 0.195 ng/ml/mg for females, respectively; P = 0.035). However, after correction for weight, the gender difference in C/D ratio dropped to 22% and significance was lost (P = 0.133). Valproate comedication was associated with a 77% increase in quetiapine plasma levels (P = 0.016). In conclusion, older age, body weight and comedication with valproate have to be considered when prescribing quetiapine. Higher plasma levels in female patients need to be replicated in larger samples.

Metabolic mechanism of quetiapine in vivo with clinical therapeutic dose

The in vivo metabolic mechanism of quetiapine (QTP) with clinical therapeutic dose was studied. Nineteen patients received multiple doses of QTP with or without concomitant erythromycin. Midazolam was given to detect enzyme activity. Plasma Concentrations of QTP, midazolam, and their metabolites were measured at specified time intervals. In presence of erythromycin, activity of CYP3A4 decreased significantly; for QTP, C(max), AUC(0-24), and t(1/2) increased significantly, CL decreased significantly, and variations in AUC(0-24) and CL showed, respectively, significant negative and positive correlation to that of CYP3A4 activity; for QTP sulfoxide (QTP-SF), C(max) and AUC(0-24) decreased significantly, t(1/2) increased significantly, and variation of t(1/2) was significantly positively correlated to that of CYP3A4 activity; for 7-hydroxy-quetiapine (QTP-H), t(1/2) increased significantly and was closely correlated to CYP3A4 activity; for 7-hydroxy-N-desalkyl-quetiapine (QTP-ND), C(max) and AUC(0-24) decreased significantly, and variation of AUC(0-24) was significantly positively correlated to that of CYP3A4 activity. In conclusion, the major metabolic pathway of QTP is sulfoxidation. CYP3A4 is the primary enzyme responsible for CYP-mediated metabolism of QTP in clinical therapy dosage in vivo. QTP sulfoxidation and N-dealkylation are mainly catalyzed by CYP3A4. 7-Hydroxylation of QTP is not mainly catalyzed by CYP3A4. The metabolism of QTP-SF and QTP-H is mainly catalyzed by CYP3A4, but QTP-ND is not by CYP3A4.

Effect of erythromycin on metabolism of quetiapine in Chinese suffering from schizophrenia

To study the effect of erythromycin on metabolism of quetiapine in Chinese suffering from schizophrenia. Nineteen patients received multiple doses of quetiapine (200 mg, twice daily) with or without co-administered erythromycin (500 mg, three times daily). Blood samples were collected at specified time intervals for determination of plasma concentrations of quetiapine and some of its metabolites. With erythromycin co-administration: for quetiapine, maximal plasma concentration (Cmax), area under concentration-time curve of 0-infinity h (AUC0-infinity) and terminal-phase elimination half-life time (t1/2) increased 68, 129 and 92%, respectively, and clearance (CL) and terminal elimination rate constant (Ke) decreased 52% and 55%, respectively; for quetiapine sulfoxide (QTP-SF), Cmax, AUC0-infinity and AUC ratio decreased 64, 23, and 70%, respectively, and t1/2 increased 211%; for 7-hydroxy-quetiapine (QTP-H), Ke and AUC ratio decreased 61% and 45%, respectively, and t1/2 increased 203%; for 7-hydroxy-N-desalkyl-quetiapine (QTP-ND), Cmax, AUC0-infinity and AUC ratio decreased 36, 40 and 71%, respectively. Erythromycin has a noticeable effect on the metabolism of quetiapine. When quetiapine is co-administered with CYP3A inhibitors such as erythromycin, the dosing regimen should be modified according to quetiapine TDM.

Pharmacokinetics of Quetiapine in Elderly Patients with Selected Psychotic Disorders

To assess the pharmacokinetics and tolerability of quetiapine in elderly patients with selected psychotic disorders. This was a multicentre, open-label, 27-day, rising multiple-dose trial. Descriptive statistics summarised plasma quetiapine concentrations and pharmacokinetic parameters by trial day. A two-way analysis of variance was used to evaluate all pharmacokinetic parameters, and 90% confidence intervals of the mean differences were calculated. Antipsychotic drugs taken prior to the study period were discontinued on day 1. Quetiapine treatment began on day 3. Doses were increased stepwise, starting at 25mg three times daily and reaching 250mg three times daily by day 21. Twelve patients (age 63-85 years) with schizophrenia, schizoaffective disorder or bipolar disorder. Key assessments included quetiapine plasma concentrations, and neurological and safety evaluations. Under steady-state conditions, the 100 and 250mg doses of quetiapine were not significantly different in terms of dose-normalised area under the plasma concentration-time curve within an 8-hour dose administration interval, or in dose-normalised minimum plasma concentration (C(min)) at the end of a dose administration interval. The morning C(min) values for the seven discrete dose amounts evaluated also increased linearly with dose. The apparent oral clearance, volume of distribution and half-life did not change as a function of dose. There were no serious adverse events. The most common adverse events were postural hypotension (n = 6), dizziness (n = 5) and somnolence (n = 4). While quetiapine was well tolerated at doses up to 250mg three times daily, the potential for reduced clearance, as well as the adverse effects of postural hypotension and dizziness, indicated that quetiapine should be introduced at lower doses and titrated at a relatively slower rate in patients > or =65 years.

D 2 and 5HT 2A receptor occupancy of different doses of quetiapine in schizophrenia: a PET study

Objective: Quetiapine is a novel antipsychotic agent with many atypical features, including low D 2 and higher 5HT 2A affinity in vitro, low propensity to induce extra-pyramidal side effects and minimal effects on prolactin levels. The purpose of this study was to investigate, using positron emission tomography (PET), the relationship between plasma concentrations of different doses of quetiapine and occupancy of D 2 and 5HT 2A receptors in schizophrenic patients. Methods: Five patients were treated with quetiapine (titrated to 750 or 450 mg/day) for 28 days, subsequently reduced weekly in a descending-dose schedule. Dopamine D 2 and 5HT 2A occupancies were determined using [ 11C] raclopride and [ 11C] N-methylspiperone as ligands, respectively, and PET imaging. Results: Mean D 2 receptor occupancies of 41 and 30% were observed at quetiapine doses of 750 and 450 mg/day. At lower dose levels no occupancy could be determined. Quetiapine induced a consistently higher degree of 5HT 2A receptor occupancy, with mean occupancies of 74 and 57% at doses of 750 and 450 mg/day, respectively. No EPS emerged during the trial and most of the pre-trial EPS resolved during the study. Conclusions: In clinically effective doses, quetiapine induced low occupancy at D 2 receptors, which is consistent with atypical antipsychotics such as clozapine, and probably explains the lack of EPS observed in this trial. Correlations between receptor occupancy and plasma concentrations of quetiapine could not be calculated, although receptor occupancy increased with higher plasma concentrations for the 450 and 750 mg doses.

Clinical pharmacokinetics of quetiapine: an atypical antipsychotic.

Quetiapine is a dibenzothiazepine derivative that has been evaluated for management of patients with the manifestations of psychotic disorders. In pharmacokinetic studies in humans, quetiapine was rapidly absorbed after oral administration, with median time to reach maximum observed plasma concentration ranging from 1 to 2 hours. The absolute bioavailability is unknown, but the relative bioavailability from orally administered tablets compared with a solution was nearly complete. Food has minimal effects on quetiapine absorption. The drug is approximately 83% bound to serum proteins. Single and multiple dose studies have demonstrated linear pharmacokinetics in the clinical dose range (up to 375mg twice daily). The drug is eliminated with a mean terminal half-life of approximately 7 hours. The primary route of elimination is through hepatic metabolism. In vitro studies show that quetiapine is predominantly metabolised by cytochrome P450 (CYP) 3A4. After administration of [14C]quetiapine, approximately 73% of the radioactivity was excreted in the urine and 21% in faeces. Quetiapine accounted for less than 1% of the excreted radioactivity. 11 metabolites formed through hepatic oxidation have been identified. Two were found to be pharmacologically active, but they circulate in plasma at 2 to 12% of the concentration of quetiapine and are unlikely to contribute substantially to the pharmacological effects of the drug. The pharmacokinetics of quetiapine do not appear to be altered by cigarette smoking. Oral clearance declines with age, and was reduced in 2 of 8 patients with hepatic dysfunction but not in patients with renal impairment. Quetiapine has no effect on the in vitro activity of CYP1A2, 2C9, 2C19, 2D6 and 3A4 at clinically relevant concentrations. The lack of effect of quetiapine on hepatic oxidation was confirmed in vivo by the lack of effect of quetiapine on antipyrine disposition. Quetiapine had no effect on serum lithium concentration. Phenytoin and thioridazine increase the clearance of quetiapine, and ketoconazole decreases clearance. No clinically significant effects of cimetidine, haloperidol, risperidone or imipramine on the pharmacokinetics of quetiapine were noted. Quetiapine dosage adjustment, therefore, may be necessary when coadministered with phenytoin, thioridazine or other potent CYP3A4 inducers or inhibitors. The relationship between the therapeutic effects and the plasma concentrations of quetiapine has been investigated in a multicentre clinical trial. There was no statistically significant association between trough plasma quetiapine concentration and clinical response as measured by traditional assessments of psychotic symptom severity. Subsequent clinical studies of the plasma concentration versus effect relationships for quetiapine may help to further define guidelines for dosage regimen design.

Analysis and pharmacokinetics of quetiapine and two metabolites in human plasma using reversed-phase HPLC with ultraviolet and electrochemical detection

A sensitive and specific HPLC assay for the measurement of the antipsychotic compound quetiapine in human plasma has been developed and validated. The assay employs a three-step liquid–liquid extraction of quetiapine and its 7-hydroxylated and 7-hydroxylated, N-dealkylated metabolites from human plasma, and utilizes ultraviolet (UV) detection of quetiapine and electrochemical detection of the metabolites. The method provides a linear response from a quantitation limit of 2.50 to 500 ng ml −1 for each analyte using 0.4 ml plasma. The assay is applicable from 500 to 5000 ng ml −1 by sample dilution with de-ionized water. The inter-assay precision of quetiapine in plasma calibration standards across 4 validation days averaged 11.9% relative standard deviation (RSD) over the range 2.50 to 500 ng ml −1, with intra-assay precision averaging 16.0% RSD and mean accuracy of 98.6% of theory. Similarly, the inter-assay precision of the 7-hydroxylated metabolite in plasma calibration standards across 4 validation days averaged 13.7% RSD over the range 2.50 to 500 ng ml −1, with intra-assay precision averaging 17.6% RSD and mean accuracy of 109% of theory. The 7-hydroxylated, N-dealkylated metabolite demonstrated inter-assay precision of 16.2% RSD, intra-assay precision of 19.9% RSD, and mean accuracy of 104% of theory over the range 2.50 to 500 ng ml −1. The present assay method was used to support a study comparing the pharmacokinetic profile of quetiapine with the time course of dopamine D 2 and serotinin 5-HT 2 receptor occupancy in the brain using positron emission tomography (PET). We describe in this paper the bioanalytical method and the plasma concentrations of quetiapine and its metabolites resulting from this study.

Pharmacokinetics of ‘seroquel’ (quetiapine) in hepatic and renal insufficiency

Objective: Quetiapine is a novel antipsychotic agent with many atypical features, including low D2 and higher 5HT2A affinity in vitro, low propensity to induce extra-pyramidal side effects and minimal effects on prolactin levels. The purpose of this study was to investigate, using positron emission tomography (PET), the relationship between plasma concentrations of different doses of quetiapine and occupancy of D2 and 5HT2A receptors in schizophrenic patients. Methods: Five patients were treated with quetiapine (titrated to 750 or 450 mg/day) for 28 days, subsequently reduced weekly in a descending-dose schedule. Dopamine D2 and 5HT2A occupancies were determined using [11C] raclopride and [11C] N-methylspiperone as ligands, respectively, and PET imaging. Results: Mean D2 receptor occupancies of 41 and 30% were observed at quetiapine doses of 750 and 450 mg/day. At lower dose levels no occupancy could be determined. Quetiapine induced a consistently higher degree of 5HT2A receptor occupancy, with mean occupancies of 74 and 57% at doses of 750 and 450 mg/day, respectively. No EPS emerged during the trial and most of the pre-trial EPS resolved during the study. Conclusions: In clinically effective doses, quetiapine induced low occupancy at D2 receptors, which is consistent with atypical antipsychotics such as clozapine, and probably explains the lack of EPS observed in this trial. Correlations between receptor occupancy and plasma concentrations of quetiapine could not be calculated, although receptor occupancy increased with higher plasma concentrations for the 450 and 750 mg doses.