Active Metabolite Dehydroaripiprazole Research Articles

Effects of the second-generation antipsychotic drugs aripiprazole and olanzapine on human adipocyte differentiation

Second-generation antipsychotics (SGAs), used as the cornerstone treatment for schizophrenia and other mental disorders, can cause adverse metabolic effects (e.g. obesity and type 2 diabetes). We investigated the effects of SGAs on adipocyte differentiation and metabolism. The presence of therapeutic concentrations of aripiprazole (ARI) or its active metabolite dehydroaripiprazole (DARI) during human adipocyte differentiation impaired adipocyte glucose uptake while the expression of gene markers of fatty acid oxidation were increased. Additionally, the use of a supra-therapeutic concentration of ARI inhibited adipocyte differentiation. Furthermore, olanzapine (OLA), a highly obesogenic SGA, directly increased leptin gene expression but did not affect adipocyte differentiation and metabolism. These molecular insights are novel, and suggest that ARI, but not OLA, may directly act via alterations in adipocyte differentiation and potentially by causing a switch from glucose to lipid utilization in human adipocytes. Additionally, SGAs may effect crosstalk with other organs, such as the brain, to exert their adverse metabolic effects.

Understanding inter-individual variability in pharmacokinetics/pharmacodynamics of aripiprazole in children with tic disorders: Individualized administration based on physiological development and CYP2D6 genotypes.

Objective: This study aims to develop a combined population pharmacokinetic (PPK) model for aripiprazole (ARI) and its main active metabolite dehydroaripiprazole (DARI) in pediatric patients with tic disorders (TD), to investigate the inter-individual variability caused by physiological and genetic factors in pharmacokinetics of ARI and optimize the dosing regimens for pediatric patients. Methods: A prospective PPK research was performed in Chinese children with TD. Totally 84 patients aged 4.83-17.33 years were obtained for the pharmacokinetic analysis. 27 CYP2D6 and ABCB1 gene alleles were detected. Moreover, the clinical efficacy was evaluated according to reduction rate of Yale Global Tic Severity Scale (YGTSS) score at the 12thweek comparing with the baseline. Monte Carlo simulations were used to evaluate and optimize dosing regimens. Results: The PPK model was established to predict the concentrations of ARI and DARI. Body weight and CYP2D6 genotype were the significant covariates affecting the clearance of ARI. The DARI/ARI metabolic ratios (MRs) of AUC24h, Cmin and Cmax at the steady state of results were ultra-rapid metabolizers (UMs) > normal metabolizers (NMs) > intermediated metabolizers (IMs). MRs could be used to distinguish UMs or IMs from other patients. The best predictor of clinical efficacy for TD was the trough concentration of ARI and the cut-off point was 101.636ng/ml. Conclusion: The pharmacokinetics of ARI and DARI in pediatric TD were significantly influenced by body weight and CYP2D6 genotype. Individualized dosing regimens were recommended for pediatric patients with TD to ensure clinical efficacy.

Therapeutic drug monitoring of aripiprazole as part of the individualization of the pharmacotherapy of schizophrenia

To personalize pharmacotherapy with aripiprazole in patients with schizophrenia via therapeutic drug monitoring (TDM). TDM of aripiprazole (ARI) and its active metabolite dehydroaripiprazole (DHA) was performed for patients diagnosed with schizophrenia (ICD-10 F20.00; F20.01; F20.02). Thirty-six parameters were assessed. To carry out TDM, the method of high-performance liquid chromatography with mass spectrometry was chosen employing a validated method. TLM was performed in a group of young patients: 26.5±10.1 years old, average weight 77.2±16.2 kg, average PANSS score 81.4±21.4, UKU score 14.5±3.9. An average ARI concentration was 18.4±7.9 mg, serum ARI concentration 417.9±362.4 ng/ml, serum DHA concentration 117.5±116.1 ng/ml and the total concentration 535.4±478.5 ng/ml. Equations of correlation dependences of concentration on dose are obtained for ARI and DHA. The results show the significant metabolism of ARI. A combined determination of the main substance and its active metabolite DHA in the patient's blood serum is advisable for correct assessment of the TLM result in patients with mental diseases.

Influence of CYP2D6 Phenotypes on the Pharmacokinetics of Aripiprazole and Dehydro-Aripiprazole Using a Physiologically Based Pharmacokinetic Approach.

Background and ObjectivesAripiprazole is an atypical antipsychotic drug that is metabolized by cytochrome P450 (CYP) 2D6 and CYP3A4, which mainly form its active metabolite dehydro-aripiprazole. Because of the genetic polymorphism of CYP2D6, plasma concentrations are highly variable between different phenotypes. In this study, phenotype-related physiologically based pharmacokinetic models were developed and evaluated to suggest phenotype-guided dose adjustments.MethodsPhysiologically based pharmacokinetic models for single dose (oral and orodispersible formulation), multiple dose, and steady-state condition were built using trial data from genotyped healthy volunteers. Based on evaluated models, dose adjustments were simulated to compensate for genetically caused differences.ResultsPhysiologically based pharmacokinetic models were able to accurately predict the pharmacokinetics of aripiprazole and dehydro-aripiprazole according to CYP2D6 phenotypes, illustrated by a minimal bias and a good precision. For single-dose administration, 92.5% (oral formulation) and 79.3% (orodispersible formulation) of the plasma concentrations of aripiprazole were within the 1.25-fold error range. In addition, physiologically based pharmacokinetic steady-state simulations demonstrate that the daily dose for poor metabolizer should be adjusted, resulting in a maximum recommended dose of 10 mg, but no adjustment is necessary for intermediate and ultra-rapid metabolizers.ConclusionsIn clinical practice, CYP2D6 genotyping in combination with therapeutic drug monitoring should be considered to personalize aripiprazole dosing, especially in CYP2D6 poor metabolizers, to ensure therapy effectiveness and safety.

Human macrophages stimulate expression of inflammatory mediators in adipocytes; effects of second-generation antipsychotics and glucocorticoids on cellular cross-talk

ObjectiveAdipose tissue inflammation and distorted macrophage-adipocyte communication are positively associated with metabolic disturbances. Some pharmacological agents, such as second-generation antipsychotics (SGAs) and synthetic glucocorticoid (GC) dexamethasone, tend to induce adverse metabolic side effects and the underlying mechanisms are not fully understood. Our work aimed to study whether SGAs and dexamethasone affect macrophage phenotype and macrophage-adipocyte communication on gene expression level. We selected the model involving THP-1-derived macrophages, polarized into M0, M1, and M2 phenotypes, and primary human mature subcutaneous adipocytes. MethodsAbdominal subcutaneous adipose tissue needle biopsies were obtained from 6 healthy subjects (4F/2M; age: 22–64 yr; BMI: 21.7–27.6 kg/m2) followed by isolation of mature adipocytes. THP-1-human monocytic cell line was used for the study. THP-1 monocytes were differentiated and polarized into M0 (naïve), M1 (classically activated), and M2 (alternatively activated) macrophages. During and after polarization the macrophages were treated for 24 h without (control) or with therapeutic and supra-therapeutic concentrations of olanzapine (0.2 µM and 2.0 µM), aripiprazole (1.0 µM and 10 µM) and its active metabolite dehydroaripiprazole (0.4 µM and 4.0 µM). Isolated mature human adipocytes were co-incubated with THP-1-derived polarized macrophages pre-treated with SGAs after their polarization. Adipocytes and macrophages were collected before and after co-culture for mRNA expression analysis of genes involved in inflammation. ResultsCo-incubation of mature human adipocytes with human macrophages, regardless of polarization, resulted in a marked induction of pro-inflammatory cytokines in adipocytes, including IL1B, IL6, TNFA, and IL10. Remarkably, it did not affect the expression of adipokines and genes involved in the regulation of energy, lipid, and glucose metabolism in adipocytes. Dexamethasone markedly reduced gene expression of pro-inflammatory cytokines in macrophages and prevented macrophage-induced inflammatory response in adipocytes. In contrast, SGAs did not affect macrophage-adipocyte communication and had a minute anti-inflammatory effect in macrophages at supra-therapeutic concentrations. Interestingly, the adipocytes co-incubated with M1 macrophages pre-treated with dexamethasone and SGAs particularly the supra-therapeutic concentration of olanzapine, reduced expression of LPL, LIPE, AKT1, and SLC2A4, suggesting that the expression of metabolic genes in adipocytes was dependent on the presence of pro-inflammatory M1 macrophages. ConclusionTogether, these data suggest that macrophages induce expression of pro-inflammatory genes in human subcutaneous adipocytes without affecting the expression of adipokines or genes involved in energy regulation. Furthermore, our findings demonstrated that SGAs and dexamethasone had a mild effect on macrophage-adipocyte communication in M1 macrophage phenotype.

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.

Concentrations of aripiprazole and dehydroaripiprazole in hair segments from deceased individuals with mental disorders

Segmental hair analysis provides information regarding previous long-term drug exposure, which is useful in the evaluation of cause of death for individuals with mental disorders. The aim was to analyze postmortem concentrations of the antipsychotic drug aripiprazole and its active metabolite dehydroaripiprazole in hair segments from individuals with known aripiprazole intake. Hair samples were collected during autopsy. Each sample was segmented into one to six 1cm segments, depending on the length of the hair shaft. Pulverized hair was extracted and analyzed using a previously published ultra-high-performance liquid chromatography–tandem mass spectrometric method. The 10th–90th percentile of aripiprazole concentrations in all hair segments (n=78) from 17 individuals were 0.024ng/mg–11ng/mg with a median of 2.3ng/mg, and the 10th–90th percentile concentrations of dehydroaripiprazole were 0.020ng/mg–11ng/mg, with a median of 2.6ng/mg, in all hair segments (n=71). The metabolite-to-parent drug ratios ranged from 0.21 to 1.5, with a median of 0.72. The administered doses were calculated for each individual based on aripiprazole prescription data and pharmacy pickups, giving dose estimates of 1mg–32mg daily. A positive significant correlation was observed between concentrations in hair and blood, whereas no trends were observed between the concentrations in hair and the estimated doses. Besides aripiprazole, other antipsychotic drugs were found in several hair segments, indicating a high degree of polypharmacy among all subjects. The present study establishes concentrations of aripiprazole and dehydroaripiprazole in hair segments from 17 deceased individuals with long-term aripiprazole use. In addition, hair analysis demonstrates the possibility of evaluating polypharmacy.

Structural Diversity of Brexpiprazole and Related Analogues: Impact on Solubility and Drug Delivery

Brexpiprazole (BPZ) is an atypical antipsychotic drug indicated for the treatment of schizophrenia and depression. Crystal form screening of BPZ resulted in the formation of three polymorphs (I, II, and III), two methanol solvates, a toluene hemisolvate, and a dihydrate. Thermal analysis and solvent-mediated conversion experiments of the three unsolvated polymorphs established that Form I is the thermodynamically stable form at ambient temperature. All three polymorphs are monotropically related, whereby Forms I and II are the most and least stable forms, respectively. Structural diversity of BPZ was compared with two chemically related analogues, aripiprazole (APZ) and its active metabolite dehydro-aripiprazole (dAPZ). Like APZ and dAPZ, BPZ was shown to form a thermodynamically stable, hydrated crystal form when exposed to an aqueous environment; however, while APZ and dAPZ were characterized as monohydrates, BPZ is a dihydrate. The crystal structure of BPZ dihydrate (S2H2O) showed two water molecules c...

An unprecedented case of dodecamorphism: the twelfth polymorph of aripiprazole formed by seeding with its active metabolite

A new polymorph of aripiprazole has been discovered, making it the most polymorphic drug to date with twelve reported anhydrous forms, and a record-breaking ninth solved crystal structure. The new form was induced by seeding with crystals of the active metabolite dehydro-aripiprazole.

DEVELOPMENT OF A SIMPLE AND SPECIFIC UHPLC ASSAY FOR THE DETERMINATION OF ARIPIPRAZOLE AND DEHYDROARDPDPRAZOLE IN RAT PLASMA

ABSTRACT A new, simple, specific, and rapid ultra high performance liquid chromatography method was developed and validated for the determination of aripiprazole and its active metabolite dehydroaripiprazole in rat plasma. The analysis was performed on a Zorbax Eclipse Plus C18 (50 mm × 2.1 mm, 1.8 µm particles) column using gradient elution with a mobile phase consisting of acetonitrile and acetate buffer (30 mM, pH 5). Plasma samples were analyzed after a simple, one-step protein precipitation with acetonitrile. The method was validated and the specificity, linearity, limit of detection, limit of quantitation, precision, accuracy, recoveries, matrix effect, stability and robustness were determined. The analytes and internal standard were separated in 3.5 min and the total analysis time including the clean-up step was 8 min. Limit of detection was 0.012 µg mL -1 and 0.009 µg mL for aripiprazole and dehydroaripiprazole, respectively. Limit of quantitation was 0.039 µg mL -1 and 0.029 µg mL for aripiprazole and dehydroaripiprazole, respectively.The intra- and inter-day assay variability was less than 2% for the analytes. The proposed method is rapid, reproducible and accurate to quantify both aripiprazole and dehydroaripiprazole. It involves a simple plasma deproteination technique using one step protein precipitation with acetonitrile. This validated method was successfully used to quantify plasma concentrations of the analytes in rat plasma.

Impact of genetic deficiencies of P-glycoprotein and breast cancer resistance protein on pharmacokinetics of aripiprazole and dehydroaripiprazole

1. We investigated how deficiencies in P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) affect the pharmacokinetics of atypical antipsychotics aripiprazole and its active metabolite (dehydroaripiprazole) using normal Friend leukemia virus strain B (FVB) mice, BCRP knockout (Bcrp[−/−]) mice, and P-gp and BCRP triple knockout (Mdr1a/1b[−/−]Bcrp[−/−]) mice.2. While plasma concentrations of aripiprazole and dehydroaripiprazole after oral administration were slightly higher in both Bcrp(−/−) and Mdr1a/1b(−/−)/Bcrp(−/−) mice than in normal FVB mice, the difference was not marked. The increase in absolute bioavailability (F) compared with normal mice (approximately 1.3-fold increase) was comparable between Bcrp(−/−) and Mdr1a/1b(−/−)/Bcrp(−/−) mice. This finding suggests that BCRP may be involved in the intestinal absorption of aripiprazole in mice, albeit with minimal contribution to absorption at best.3. In contrast, the brain-to-plasma concentration ratio (Kp,brain) for aripiprazole and dehydroaripiprazole after oral administration was significantly higher in Mdr1a/1b(−/−)/Bcrp(−/−) mice than in normal mice, whereas Bcrp(−/−) mice exhibited Kp,brain values similar to those in normal mice. In addition, the Kp,brain values in Mdr1a/1b(−/−)/Bcrp(−/−) mice were not drastically different from those previously reported in Mdr1a/1b(−/−) mice, suggesting that brain penetration of aripiprazole and dehydroaripiprazole can be affected by P-gp, but with little synergistic effect of BCRP.

Effects of aripiprazole and its active metabolite dehydroaripiprazole on the activities of drug efflux transporters expressed both in the intestine and at the blood–brain barrier

The inhibition potencies of aripiprazole and its active metabolite, dehydroaripiprazole, on the activities of human multidrug resistance protein 1 (MDR1/ABCB1; P-glycoprotein), breast cancer resistance protein (BCRP/ABCG2) and multidrug resistance-associated protein 4 (MRP4/ABCC4), that are drug efflux transporters expressed both in the intestine and at the blood-brain barrier (BBB), were investigated. Aripiprazole and dehydroapripiprazole showed relatively strong inhibitory effects on human MDR1 with IC(50) values of 1.2 and 1.3 µm in human MDR1-transfected Mardin-Darby canine kidney (MDCKII-MDR1) cells, respectively. The inhibition potencies of other atypical antipsychotics (risperidone, paliperidone, olanzapine and ziprasidone) for human MDR1 were also evaluated using the same in vitro experimental system and IC(50) values were more than 10-fold higher than those of the two compounds. Aripiprazole and dehydroaripiprazole also had inhibition potencies against human BCRP with IC(50) values of 3.5 and 0.52 µm, respectively. The ratios of steady-state unbound concentrations of aripiprazole and dehydroaripiprazole to their IC(50) values against human MDR1 and BCRP activities were less than 0.1, whereas the theoretically maximum gastrointestinal concentration of aripiprazole ([I](2) ) to its IC(50) values was much higher than the cut-off value of 10, proposed by the International Transporter Consortium (ITC) and the Food and Drug Administration (FDA). In contrast, aripiprazole and dehydroaripiprazole showed almost no inhibitory effect against the activity of human MRP4. These findings indicate that aripiprazole is unlikely to cause drug-drug interactions (DDIs) at the BBB when co-administered with substrate drugs of these drug transporters investigated. However, interactions at the intestinal absorption process may be of concern.

Aripiprazole and Dehydroaripiprazole Plasma Concentrations and Clinical Responses in Patients With Schizophrenia

Aripiprazole is widely used to treat schizophrenia. Plasma levels of aripiprazole and its active metabolite dehydroaripiprazole and their clinical responses in patients were explored. Forty-five (male/female: 19/26) patients with schizophrenia were treated with aripiprazole after a washout period of at least 3 days. There was no concomitant psychotropic except benzodiazepines for insomnia. The Positive and Negative Syndrome Scale (PANSS) was used to measure the clinical response at baseline and at weeks 2, 4, and 6. Blood was drawn at week 6 to measure the plasma concentrations of aripiprazole and dehydroaripiprazole. Patients with a PANSS score that decreased by more than 20% were defined as responders after 6 weeks of treatment. There was no difference in baseline PANSS scores or the daily dosage used between responders (n = 28) and nonresponders (n = 17) (15.0 ± 5.9 vs 12.9 ± 6.9 mg, respectively; P = 0.203). The responders showed a trend toward a higher plasma concentration of aripiprazole than nonresponders (234.4 ± 156.7 vs 163.5 ± 77.2 ng/mL, respectively; P = 0.117) and a significantly higher plasma concentration of dehydroaripiprazole (101.6 ± 58.0 vs 66.0 ± 48.4, respectively; P = 0.023). Higher plasma concentrations of aripiprazole and its active metabolite dehydroaripiprazole were noted in responders than nonresponders. Compared with Western patients, Oriental patients had higher plasma concentrations of aripiprazole and dehydroaripiprazole at the same dose. We suggest that therapeutic drug monitoring of aripiprazole will help improve the response in clinical practice.

Pharmacokinetics of acute and sub-chronic aripiprazole in P-glycoprotein deficient mice

Background P-glycoprotein (P-gp), an efflux transporter localized in the blood–brain barrier, limits the access of multiple xenobiotics to the central nervous system (CNS). For the new antipsychotic aripiprazole and its active metabolite dehydroaripiprazole differences in disposition in blood and brain were investigated after acute and sub-chronic administration in a P-gp knockout mouse model. Methods Serum and brain concentrations of both drugs were measured at several time points 1–24 h after i.p. injection of 10 mg/kg aripiprazole and after 11 days of sub-chronic administration in several tissues. Moreover, the expression of P-gp was determined by Western blot analysis after sub-chronic administration of the drug. Results In both wild type and abcb1ab (−/−) mice concentration of aripiprazole in brain were up to 9 fold higher than in serum. For dehydroaripiprazole the mean brain to serum ratios were below two. Brain to serum concentrations of both substances were significantly higher after acute and sub-chronic administration in connection to the expression of P-gp indicated by higher levels in abcb1ab (−/−) mice especially for dehydroaripiprazole. Sub-chronic aripiprazole treatment in WT animals had no effect on P-gp expression in the blood–brain barrier. Conclusions Aripiprazole and, even more pronounced its active metabolite dehydroaripiprazole could be identified as substrates of P-gp. The efflux transporter P-gp must therefore be considered as a relevant factor that contributes to wanted or unwanted clinical effects in patients treated with aripiprazole.

Development of an LC–MS/MS method for the simultaneous quantification of aripiprazole and dehydroaripiprazole in human plasma

A selective, sensitive, and accurate liquid chromatography–tandem mass spectrometry (LC–MS/MS) method for the simultaneous determination of aripiprazole and its active metabolite dehydroaripiprazole in human plasma has been developed using papaverine as internal standard (IS). LC–MS/MS analysis was carried out on a Finnigan LC–TSQ Quantum mass spectrometer using positive ion electrospray ionization (ESI +) and selected reaction monitoring (SRM). The assays for aripiprazole and dehydroaripiprazole were linear over the ranges of 0.1 to 600 ng/ml and 0.01 to 60 ng/ml, respectively. The average recoveries in plasma samples both were better than 85%. The intra- and interrun precision and accuracy values were found to be within the assay variability criteria limits according to the US Food and Drug Administration guidelines. The developed method was proved to be suitable for use in a clinical pharmacokinetic study after a single oral administration of a 5-mg aripiprazole tablet in healthy Chinese volunteers.

Pharmacokinetics and Tolerability of Intramuscular, Oral and Intravenous Aripiprazole??in Healthy Subjects and in??Patients??with Schizophrenia

Patients with schizophrenia or bipolar disorder who are experiencing acute behavioural emergencies often require intramuscular injection of antipsychotics for rapid symptom resolution. The efficacy and tolerability of intramuscular aripiprazole injection has been established in agitated inpatients with schizophrenia or bipolar I disorder. The main objective of the two clinical pharmacology studies reported here was to evaluate the pharmacokinetics of aripiprazole after intramuscular dosing in healthy subjects and in patients with schizophrenia, and after intravenous and oral dosing in healthy subjects. Study 1 was an open-label, randomized, three-treatment crossover study in healthy subjects (n = 18) to assess the bioavailability and pharmacokinetics of intramuscular aripiprazole 5 mg and oral aripiprazole 5 mg relative to intravenous aripiprazole 2 mg. Study 2 was an open-label, nonrandomized, escalating-dose study in patients with schizophrenia (n = 32) to evaluate the pharmacokinetics of intramuscular aripiprazole across a range of doses (from 1 mg to 45 mg). The noncompartmental pharmacokinetic parameters for plasma concentrations of aripiprazole and its active metabolite dehydro-aripiprazole were determined. Safety and tolerability data are also summarized. In study 1, the geometric mean values for the absolute bioavailability of aripiprazole following oral and intramuscular administration were 0.85 and 0.98, respectively. Intramuscular aripiprazole demonstrated more rapid attainment of plasma aripiprazole concentrations than oral aripiprazole (78% and 5% of peak plasma concentration [C(max)] values at 0.5 hours postdose, respectively). The area under the plasma concentration-time curve (AUC) in the first 2 hours was 90% higher after intramuscular administration than after oral administration. For dehydro-aripiprazole, the AUC over the collection interval values were higher, the times to reach the C(max) values were later and the C(max) values were similar for the intramuscular and oral formulations. In study 2, the proportionality of the C(max) and AUC to doses ranging from 1 mg to 45 mg suggests a linear pharmacokinetic profile for intramuscular aripiprazole. More rapid absorption was observed following intramuscular aripiprazole injection than following oral dosing. These results support the recently reported efficacy of intramuscular aripiprazole for managing agitation in patients with schizophrenia or bipolar I disorder.

Serum levels of aripiprazole and dehydroaripiprazole, clinical response and side effects

Aripiprazole, a novel antipsychotic drug, is metabolized by CYP3A4 and CYP2D6 forming mainly its active metabolite dehydroaripiprazole. In this study, aripiprazole and dehydroaripiprazole serum levels of psychiatric patients were measured and related to dose, comedication, and clinical effects including therapeutic and side effects. Patients were treated with mean doses of 20±8 mg/day of aripiprazole (median 15 mg, range 7.5–60 mg). Serum levels correlated significantly with the dose (r=0.419; P<0.01), with a mean value of aripiprazole of 214±140 ng/ml. Mean concentrations of the active metabolite dehydroaripiprazole amounted to 40% of the parent compound. Comedication with CYP3A4 and CYP2D6 inducers or inhibitors changed serum levels up to 51%. Improvement was best in patients with a serum level between 150 to 300 ng/ml. No or only mild side effects were detected in patients, with aripiprazole plasma concentrations between 110 and 249 ng/ml. A total of 32% of the patients who received no other antipsychotic drug besides aripiprazole reported side effects; tension being the most frequent one. Since serum levels of aripiprazole and dehydroaripiprazole were highly variable between individuals, and distinct ranges were associated with good therapeutic response and minimal side effects, it seems likely that therapeutic drug monitoring can be helpful to improve the antipsychotic drug therapy.

Impact of the CYP2D6 genotype on steady-state serum concentrations of aripiprazole and dehydroaripiprazole

Aripiprazole is an atypical antipsychotic drug which is metabolized by the polymorphic enzyme cytochrome P450 2D6 (CYP2D6). The aim of the present study was to investigate the impact of the CYP2D6 genotype on serum concentrations of aripiprazole (ARI) and to determine the sum of ARI and the active metabolite dehydroaripiprazole (DARI) in psychiatric patients. Data on steady-state serum concentrations and the CYP2D6 genotypes of patients treated with ARI were extracted from a routine therapeutic drug monitoring database. The 62 patients included in the analysis were stratified into the following subgroups according to CYP2D6 genotype: *1/*1 (homozygous extensive metabolizers, EMs; n = 37), *1/*3-6 (heterozygous extensive metabolizers, HEMs; n = 17) and *3-6/*3-6 (poor metabolizers, PMs; n = 8). Dose-adjusted serum concentrations (C/D ratios) of ARI and ARI + DARI were compared between the subgroups. The median serum concentration of ARI was 1.7-fold higher in PMs than in EMs (45.5 vs. 26.3 nM/mg, p < 0.01). The observed serum concentration of the active sum of ARI + DARI was 1.5-fold higher in PMs than in EMs (53.9 vs. 37.0 nM/mg, p < 0.05). Numerical differences in serum concentrations between HEMs and EMs were less pronounced, but statistically significant for both ARI (p < 0.05) and ARI + DARI (p < 0.05). The present study demonstrates that serum concentrations of both ARI and the active sum of ARI + DARI in psychiatric patients were significantly affected by CYP2D6 genotype. The observed differences in median C/D ratios indicate that PMs typically need 30-40% lower doses to achieve a similar steady-state serum concentration as EMs.

Multi-Drug-Resistance proteins affect antipsychotic treatment: in vivo effects of aripiprazole

Multi Drug Resistance (MDR) carriers in the Blood-Brain-Barrier (BBB) protect the brain from pharmacological tissue damage. Of all of the MDR xenobiotic efflux pumps highly expressed in the BBB p-glycoprotein (p-gp, MDR1) handles the largest fraction of commonly prescribed drugs. We investigated the role of p-gp on metabolic (pharmacokinetic) and behavioral (pharmacodynamic) effects of aripiprazole (ari) in a p-gp k.o. mouse model (mdr1a/b -/-). Wild type and transgenic mice were acutely treated (i.p.) with either aripiprazole or its active metabolite dehydroaripiprazole (d-ari), or saline. Blood serum and brain tissue levels were measured 1,3,6,9, and 24h after injection. Behavioral changes were analysed on a rotarod and in the radial water maze learning task 0.5h after treatment. Kinetic investigation revealed significant differences (p<0.05) between both genotypes for ari (10mg/kg) and for d-ari in both serum and brain tissue. In wild type mice both substances affected locomotor behavior significantly (ari 1 and 5mg/kg; d-ari 1mg/kg). In transgenic mice this effect was significantly increased. For learning behavior (ari/d-ari 1mg/kg) the difference between both genotypes was not as prominent as on the rotarod. These results give strong evidence that aripiprazole as well as its active metabolite dehydroaripiprazole are substrates of p-gp and that this has consequences for clinical outcome.

Pharmacokinetic Variability of Aripiprazole and the Active Metabolite Dehydroaripiprazole in Psychiatric Patients

Aripiprazole is a new atypical antipsychotic drug with a partial agonist activity at dopamine 2 and serotonin 1A receptors. The metabolism of aripiprazole involves both cytochrome P450 2D6 (CYP2D6) and CYP3A4. This study investigated the pharmacokinetic variability of aripiprazole and the active metabolite dehydroaripiprazole on the basis of 155 drug monitoring samples from psychiatric patients treated with therapeutic doses of aripiprazole (10-30 mg/day). Serum concentrations of drug and metabolite were determined by liquid chromatographic and tandem mass spectrometric detection. Pharmacokinetic variability was expressed as the range in concentration/dose (C/D) ratios, and the effect of sex and occasionally coprescribed CYP2D6 or CYP3A4 inhibitors/inducers was studied. In addition, the dose-concentration relationship and combined interquartile range of concentrations obtained at low dose (10-15 mg/day) and high dose (20-30 mg/day) were described. Individual C/D ratios ranged 37-fold for aripiprazole, 78-fold for dehydroaripiprazole, and 27-fold for the active sum of aripiprazole + dehydroaripiprazole. Median C/D ratios in male and female patients differed by less than 15%, and none of the differences were significant (P > 0.14). Cases of concurrent CYP3A4 inducers/inhibitors were not found, but three patients were coprescribed the potent CYP2D6 inhibitors paroxetine or fluoxetine. No consistent difference in C/D ratio was observed in these three patients compared with the rest of the patients. There was a proportional dose-concentration relationship in the population, and the combined interquartile ranges were 230 to 960 nmol/L for aripiprazole and 330 to 1210 nmol/L for aripiprazole + dehydroaripiprazole. In conclusion, pharmacokinetic variability of aripiprazole is extensive in psychiatric patients but apparently not dependent on dose or sex. The variability of the pharmacologic active sum of aripiprazole + dehydroaripiprazole is 25% to 30% less than aripiprazole, suggesting that variability of aripiprazole is partly determined by metabolism to dehydroaripiprazole.