A Nanoemulgel for Nose-to-Brain delivery of Quetiapine - QbD-Enabled formulation development & in-vitro characterization.

Second-generation antipsychotics, quetiapine hemifumarate (QF), exhibited highly active against negative and positive signs of psychosis. However, contemporary reports have shown that long-term therapy with QF causes lethal thrombocytopenia and leukopenia. Hence, to circumvent the drawbacks of available therapies, the current work aimed to design a QF-loaded biodegradable nanoemulsion (QF-NE) with suitable surface charge modification by poloxamer-chitosan and evaluate its targeting efficiency against RPMI-2650 cell lines. QF-loaded poloxamer-chitosan in-situ gel (QF-Nanoemulgel) was formulated through the O/W emulsification aqueous titration technique and optimized using the QbD approach. Optimized QF-Nanoemulgel subjected to evaluate for globule size, PDI, zeta potential, %T, viscosity, %EE, and ex-vivo mucoadhesive strength were found to be 15.0 ± 0.3 nm, 0.05 ± 0.001, -18.3 ± 0.2 mV, 99.8 ± 0.8 %, 13.5 ± 2.1 cP, 69.0 ± 1.5 %, and 43.7 ± 1.5 g, respectively. QF-Nanoemulgel revealed sustained release and obeyed zero-order kinetics compared to QF-NE and QF-suspension. Additionally, nanoformulations treated blood samples did not cause hemolytic activity compared to drug and negative control after 10 h treatment. Further, in-vitro cytotoxicity, cellular uptake, and permeation of 12.5 and 25 µM QF-Nanoemulgel were assessed on RPMI-2650 cells and discovered nontoxic with 0.55 ± 0.02 µg and 1.1 ± 0.04 µg cellular permeation, respectively, which ensured the safety and potency of QF-Nanogel. Current research revealed the successful development of intranasal QF-Nanoemulgel as a novel dosage form for the safe and effective delivery of QF in schizophrenia patients.

Quetiapine Shortens the Lifespan of Caenorhabditis elegans through DOP-2, DAF-2 and RSKS-1.

Recent studies implicate a key role of dopamine signaling in lifespan regulation. Our previous study found that quetiapine, an atypical antipsychotic drug that has antagonistic activity on dopamine D2-like receptors (D2Rs), shortened the lifespan of Caenorhabditis elegans (C. elegans). However, the detailed mechanism of this effect was not clear. In the present study, we evaluate the effect of quetiapine on aging and explore its underlying molecular mechanism. The results show that quetiapine shortened healthspan in C. elegans. The lifespan-shortening effect is dependent on DOP-2, a D2R expressed in worms. Quetiapine shortens lifespan through the C. elegans insulin and IGF-1 receptor DAF-2, but not the downstream Akt pathway. Quetiapine-induced lifespan reduction is dependent on RSKS-1, a key protein kinase that functions in mTOR signaling. In addition, the quetiapine effect is also related to mitochondrial function. These findings further support the key role of dopamine signaling in lifespan regulation and promote our insight into the mechanism of action of antipsychotic drugs.

The Influence of Prenatal Exposure to Quetiapine Fumarate on the Development of Dopaminergic Neurons in the Ventral Midbrain of Mouse Embryos.

The effects of second-generation antipsychotics on prenatal neurodevelopment, apoptotic neurodegeneration, and postnatal developmental delays have been poorly investigated. Even at standard doses, the use of quetiapine fumarate (QEPF) in pregnant women might be detrimental to fetal development. We used primary mouse embryonic neurons to evaluate the disruption of morphogenesis and differentiation of ventral midbrain (VM) neurons after exposure to QEPF. The dopaminergic VM neurons were deliberately targeted due to their roles in cognition, motor activity, and behavior. The results revealed that exposure to QEPF during early brain development decreased the effects of the dopaminergic lineage-related genes Tyrosine hydroxylase(Th), Dopamine receptor D1 (Drd1), Dopamine transporter (Dat), LIM homeobox transcription factor 1 alfa (Lmx1a), and Cell adhesion molecule L1 (Chl1), and the senescent dopaminergic gene Pituitary homeobox 3 (Pitx3). In contrast, Brain derived neurotrophic factor (Bdnf) and Nuclear receptor-related 1 (Nurr1) expressions were significantly upregulated. Interestingly, QEPF had variable effects on the development of non-dopaminergic neurons in VM. An optimal dose of QEPF (10 µM) was found to insignificantly affect the viability of neurons isolated from the VM. It also instigated a non-significant reduction in adenosine triphosphate formation in these neuronal populations. Exposure to QEPF during the early stages of brain development could also hinder the formation of VM and their structural phenotypes. These findings could aid therapeutic decision-making when prescribing 2nd generation antipsychotics in pregnant populations.

Investigating and Resolving Cardiotoxicity Induced by COVID-19 Treatments using Human Pluripotent Stem Cell-Derived Cardiomyocytes and Engineered Heart Tissues.

Coronavirus disease 2019 continues to spread worldwide. Given the urgent need for effective treatments, many clinical trials are ongoing through repurposing approved drugs. However, clinical data regarding the cardiotoxicity of these drugs are limited. Human pluripotent stem cell-derived cardiomyocytes (hCMs) represent a powerful tool for assessing drug-induced cardiotoxicity. Here, by using hCMs, it is demonstrated that four antiviral drugs, namely, apilimod, remdesivir, ritonavir, and lopinavir, exhibit cardiotoxicity in terms of inducing cell death, sarcomere disarray, and dysregulation of calcium handling and contraction, at clinically relevant concentrations. Human engineered heart tissue (hEHT) model is used to further evaluate the cardiotoxic effects of these drugs and it is found that they weaken hEHT contractile function. RNA-seq analysis reveals that the expression of genes that regulate cardiomyocyte function, such as sarcomere organization (TNNT2, MYH6) and ion homeostasis (ATP2A2, HCN4), is significantly altered after drug treatments. Using high-throughput screening of approved drugs, it is found that ceftiofur hydrochloride, astaxanthin, and quetiapine fumarate can ameliorate the cardiotoxicity of remdesivir, with astaxanthin being the most prominent one. These results warrant caution and careful monitoring when prescribing these therapies in patients and provide drug candidates to limit remdesivir-induced cardiotoxicity.

Quetiapine attenuates the acquisition of morphine-induced conditioned place preference and reduces ERK phosphorylation in the hippocampus and cerebral cortex.

Background: Quetiapine is an atypical antipsychotic that antagonizes dopamine and serotonin receptors. It has been suggested that quetiapine can be used to treat substance use disorders, including opioid use disorder. Opioids modulate dopaminergic functions associated with conditioned reinforcement and these effects can be measured via the conditioned place preference (CPP) paradigm. Opioids' unconditioned effects are regulated by several proteins, including extracellular signal-regulated kinase (ERK) and cAMP-responsive element-binding (CREB).Objective: To assess the effect of quetiapine on morphine-induced CPP and motor activity levels, and on the levels of ERK and CREB proteins in the hippocampus and cerebral cortex.Methods: 42 male rats were exposed to a CPP protocol, in which they underwent a conditioning paradigm with saline, quetiapine (40 mg/kg), morphine (10 mg/kg), morphine plus quetiapine (10, 20, or 40 mg/kg), or morphine plus memantine (7.5 mg/kg, a positive control drug) (n = 6 per group). The rats were tested for CPP and exploratory activity. Levels of ERK and CREB proteins in the hippocampus and cerebral cortex were also measured.Results: Quetiapine co-administered with morphine inhibited morphine-induced CPP [F (6, 70) = 11.67, p < .001] and morphine's effects on motor activity (p < .001). Morphine enhanced ERK phosphorylation in the hippocampus (p < .001) and cerebral cortex (p < .001), an effect inhibited by quetiapine.Conclusion: Quetiapine attenuates morphine-induced CPP and locomotion and these effects are associated with a reduction of ERK phosphorylation in the hippocampus and cerebral cortex. These results suggest that quetiapine should be further explored as a potential treatment for opioid use disorder.

Effects of quetiapine administration on sperm quality and testicular histology.

Quetiapine is one of the most commonly prescribed antipsychotics to treat schizophrenia in adults, in particular. In this study, quetiapine's effects were assessed on healthy sperm production in rats at repeated-pharmacological doses. Additionally, the effects of quetiapine on oxidative status and hormonal balance were also evaluated in rats. Quetiapine was administered to rats orally at 10, 20, and 40 mg/kg body weight doses for 28 days. At the end of this period, body and organ weights were measured, sperm concentration, motility, and morphology were determined, sperm damage was assessed, and histopathological analysis of testicular tissue was performed. Additionally, serum FSH, LH, and testosterone levels as male reproductive hormones were measured. Catalase, superoxide dismutase, glutathione, and malondialdehyde levels were determined for evaluating the oxidative status of testicular tissue. The findings obtained in this study showed that relative epididymis weights and sperm concentration decreased and abnormal sperm morphology increased in quetiapine-administered rats. Irregularity of typical architecture of the seminiferous tubules and germinal cell disorganization was observed in testicular sections of 20 and 40 mg/kg quetiapine-administered rats. Further, serum LH and testosterone levels decreased in 20 and 40 mg/kg quetiapine-administered rats. Additionally, decreased catalase and superoxide dismutase activities in testicular tissue of quetiapine-administered rats and increased malondialdehyde levels in testicular tissue of 40 mg/kg quetiapine-administered rats were measured. In conclusion, quetiapine treatment decreased sperm quality, altered hormone levels, and induced oxidative stress may be considered potential contributors to this adverse effect.

Severe Adverse Drug Reactions to Quetiapine in Two Patients Carrying CYP2D6*4 Variants: A Case Report.

We report two cases of patients who developed severe adverse drug reactions including persistent movement disorders, nausea, and vertigo during treatment with quetiapine at maximum daily doses ranging between 300 and 400 mg. The extensive hepatic metabolism of quetiapine is mainly attributed to cytochrome P450 3A4 (CYP3A4). However, there is recent evidence supporting the idea of CYP2D6 playing a role in the clearance of the quetiapine active metabolite norquetiapine. Interestingly, both patients we are reporting of are carriers of the CYP2D6*4 variant, predicting an intermediate metabolizer phenotype. Additionally, co-medication with a known CYP2D6 inhibitor and renal impairment might have further affected quetiapine pharmacokinetics. The herein reported cases could spark a discussion on the potential impact of a patient's pharmacogenetic predisposition in the treatment with quetiapine. However, further studies are warranted to promote the adoption of pharmacogenetic testing for the prevention of drug-induced toxicities associated with quetiapine.

Quetiapine promotes oligodendroglial process outgrowth and membrane expansion by orchestrating the effects of Olig1.

Oligodendroglial lineage cells go through a series of morphological changes before myelination. Prior to myelination, cell processes and membrane structures enlarge by approximately 7,000 times, which is required to support axonal wrapping and myelin segment formation. Failure of these processes leads to maldevelopment and impaired myelination. Quetiapine, an atypical antipsychotic drug, was proved to promote oligodendroglial differentiation and (re)myelination, pending detailed effects and regulatory mechanism. In this study, we showed that quetiapine promotes morphological maturation of oligodendroglial lineage cells and myelin segment formation, and a short-term quetiapine treatment is sufficient to induce these changes. To uncover the underlying mechanism, we examined the effect of quetiapine on the Oligodendrocyte transcription factor 1 (Olig1). We found that quetiapine upregulates Olig1 expression level and promotes nuclear Olig1 translocation to the cytosol, where it functions not as a transcription modulator, but in a way that highly correlates with oligodendrocyte morphological transformation. In addition, quetiapine treatment reverses the negative regulatory effect of the Olig1-regulated G protein-coupled receptor 17 (GPR17) on oligodendroglial morphological maturation. Our results demonstrate that quetiapine enhances oligodendroglial differentiation and myelination by promoting cell morphological transformation. This would shed light on the orchestration of oligodendroglia developmental mechanisms, and provides new targets for further therapeutic research.

Unmetabolized quetiapine exerts an in vitro effect on innate immune cells by modulating inflammatory response and neutrophil extracellular trap formation.

Quetiapine is an antipsychotic drug that is used to treat psychiatric and neurological disorders. Despite its efficiency and low-toxicity, quetiapine administration has been associated with undesirable side effects such as the development of low-grade inflammatory disorders and neutropenia states. As the liver rapidly metabolizes quetiapine to metabolites, the non-metabolized part of this molecule might play a role in immune alterations. In an in vitro study, this hypothesis was tested by exposing activated and inactivated RAW-264.7 macrophages and human neutrophils to unmetabolized quetiapine (u-QUE). Based on our findings, u-QUE was not cytotoxic to these cells. u-QUE differentially modulates macrophages according to their activation states. In inactivated macrophages, u-QUE induced a proinflammatory state as observed by an increase in cellular proliferation; increased levels of oxidative molecules (nitric oxide and superoxide), protein levels, and gene overexpression of proinflammatory cytokines (IL-1ß, IL-6, and TNF-α); and decreased levels of IL-10, an anti-inflammatory cytokine. Conversely, on phytohemagglutinin (PHA)-activated macrophages, u-QUE exerted an anti-inflammatory effect. u-QUE induced neutrophil extracellular trap (NET) formation and increased the sensitivity of the neutrophils previously activated by exposure to dead yeast cells for NET formation. These results confirm the effect of quetiapine on macrophage and neutrophil function, which may be associated with the side effects of this psychopharmaceutical agent.

Optimization and in vivo evaluation of quetiapine-loaded transdermal drug delivery system for the treatment of schizophrenia.

The prevailing studies were carried out to formulate and optimize the quetiapine transdermal matrix patch by the usage of Box-Behnken design for ameliorated bioavailability when contrasted with conventional drug delivery. The Box-Behnken design with three-level and three-factor was utilized to explore the intermingle impact of critical attributes on tensile strength, in vitro drug release, and flux. Optimized formulation was characterized for Fourier transform infrared, differential scanning calorimetry, in vivo pharmacokinetics, and skin irritation along with stability studies. The inference of the finalized batch (F14) depicted the flux of 51.81 ± 0.32 µg/h/cm2, TS of 6.46 ± 0.56 MPa, and the % drug release after 20 h of 82.98 ± 1.48% with no remarkable variation even after 6 months stability studies. Correlation between predicted and the observed values of the dependent variables was very closer. Optimized quetiapine transdermal patch did not exert any symptoms of skin irritation. The bioavailability of quetiapine was enhanced almost 4.59 times after topical delivery when contrasted with the conventional dosage form. The outputs of the research work divulged that the developed matrix patch of quetiapine for transdermal drug delivery can be a propitious opportunity that affords effective treatment of schizophrenia. Novelty statement The oral route is not suitable for the drugs having extensive first-pass metabolism which leads to reduced bioavailability. For the parenteral route, invasiveness causes the patient noncompliance while sterility contributes to the cost factor. Moreover, the treatment of schizophrenic patients is a challenging task for caregivers and doctors. Hence, the transdermal patch of quetiapine was developed to bypass the biotransformation of drugs and thereby to enhance the bioavailability as well as to provide sustained drug delivery which ultimately reduces the dosage frequency.

A Validated Method for the Simultaneous Determination of Quetiapine, Clozapine and Mirtazapine in Postmortem Blood and Tissue Samples.

Psychotropic drugs are regularly present in cases of sudden, unexpected death. Such drugs also tend to express significant postmortem redistribution. To facilitate further investigation of this phenomenon, reliable quantitative methods applicable to multiple biological matrices are needed. We present a validated ultra-performance liquid chromatography-tandem mass spectrometry method for the simultaneous quantification of quetiapine, clozapine and mirtazapine in postmortem whole blood, skeletal muscle, brain tissue and liver tissue using high-performance liquid chromatography-tandem mass spectrometry. Sample preparation was performed using liquid-liquid extraction. The validated ranges were 3.8-1534, 16-1960 and 13-1060 µg/L for quetiapine, clozapine and mirtazapine, respectively. Within-run and between-run accuracy (87.4-122%) and precision (CV 1.5-8.9%), matrix effects (95-101%) and recovery (35.7-92%) were validated at two concentration levels; 5.8 and 1227 µg/L for quetiapine, 25 and 1568 µg/L for clozapine and 20 and 849 µg/L for mirtazapine. Stability in a 10°C environment was assessed for treated samples of brain, liver and muscle tissue, showing deviations in analyte concentrations ranging from -8% to 9% after 3 days. The analyte concentrations in treated samples of whole blood stored at 4°C deviated by <5% after 5 days. The method was applied in three forensic autopsy cases implicating quetiapine, clozapine and mirtazapine, respectively, in supratherapeutic concentrations.

A novel welfare and scientific approach to conducting dog metabolism studies allowing dogs to be pair housed.

Metabolism cages are designed to conduct absorption, distribution, metabolism and excretion (ADME) studies, enabling an 'excretion balance' scientific objective to be met. Historically, the design of dog metabolism cages has involved single housing. This type of housing has limitations for normal social behaviours and has been largely unchanged for 25-30 years. Improving animal welfare is a focus area for the authorities as well as the industry throughout the European Union. A collaboration was developed between Novo Nordisk and Covance to enhance the design of metabolism cages, allowing dogs to be pair housed. The purpose of the study was to compare excretion balance data from pair-housed and singly housed dogs in order to demonstrate that conducting excretion balance studies with a pair-housing design improves animal welfare without compromising the scientific integrity of the study. A radiolabelled test compound, [14C]-Quetiapine, was selected for this investigation based on its excretion profile. The assessment of the dogs' stress levels was investigated by measuring the levels of serum cortisol as an indicative biomarker. Results were inconclusive due to large variations in cortisol levels. However, dogs appeared calmer in the pair-housing setting. The overall mean recovery (±standard deviation) for pair-housed animals (94.0 ± 0.66% of the dose) was equivalent to that from singly housed dogs (93.0 ± 2.29%). Based on these data, we conclude that pair housing of dogs for future metabolism ADME studies does not compromise the scientific integrity, and therefore is a major progression in the design of these studies, enhancing welfare.

Effects of norquetiapine, the active metabolite of quetiapine, on cloned hERG potassium channels.

Quetiapine is an atypical antipsychotic drug that is widely used for the treatment of schizophrenia. It is mainly metabolized by a cytochrome P450 system in the liver. Norquetiapine is a major active metabolite in humans with a pharmacological profile that differs distinctly from that of quetiapine. We used the whole-cell patch-clamp technique to investigate the effects of norquetiapine on hERG channels that are stably expressed in HEK cells. Quetiapine and norquetiapine inhibited the hERG tail currents at -50mV in a concentration-dependent manner with IC50 values of 8.3 and 10.8µM, respectively, which suggested equal potency. The block of hERG currents by norquetiapine was voltage-dependent with a steep increase over a range of voltages for channel activation. However, at more depolarized potentials where the channels were fully activated, the block by norquetiapine was voltage-independent. The steady-state inactivation curve of the hERG currents was shifted to the hyperpolarizing direction in the presence of norquetiapine. Norquetiapine did not produce a use-dependent block. A fast application of norquetiapine inhibited the hERG current elicited by a 5s depolarizing pulse to +60mV, which fully inactivated the hERG currents, suggesting an inactivated-state block. During a repolarizing pulse wherein the hERG current was slowly deactivated, albeit remaining in an open state, a fast application of norquetiapine rapidly and reversibly inhibited the open state of the hERG current. Our results indicated that quetiapine and norquetiapine had equal potency in inhibiting hERG tail currents. Norquetiapine inhibited the hERG current by preferentially interacting with the open and/or inactivated states of the channels.

Bio-shielding In Situ Forming Gels (BSIFG) Loaded With Lipospheres for Depot Injection of Quetiapine Fumarate: In Vitro and In Vivo Evaluation.

Quetiapine fumarate (QF), an anti-schizophrenic drug, suffers from rapid elimination and poor bioavailability due to extensive first-pass effect. Intramuscularly (IM) injected lipospheres were designed to enhance the drug's bioavailability and extend its release. A central composite design was applied to optimize the liposphere preparation by a melt dispersion technique using Compritol® 888 ATO or glyceryl tristearate as lipid component and polyvinyl alcohol as surfactant. Lipospheres were evaluated for their particle size, entrapment efficiency, and in vitro release. The optimized QF lipospheres were prepared using a Compritol® 888 ATO fraction of 18.88% in the drug/lipid mixture under a stirring rate of 3979 rpm. The optimized lipospheres were loaded into a thermoresponsive in situ forming gel (TRIFG) and a liquid crystalline in situ forming gel (LCIFG) to prevent in vivo degradation by lipases. The loaded gels were re-evaluated for their in vitro release and injectability. Bioavailability of QF from liposphere suspension and bio-shielding in situ gels loaded with QF lipospheres were assessed in rabbits compared to drug suspension. Results revealed that the AUC0-72 obtained from the liposphere-loaded TRIFG was ∼3-fold higher than that obtained from the aqueous drug suspension indicating the bio-shielding effect of Poloxamer® 407 gel to inhibit the biodegradation of the lipospheres prolonging the residence of the drug in the muscle for higher absorption. Our results propose that bio-shielding in situ Poloxamer® 407 gels loaded with lipospheres is promising for the development of IM depot injection of drugs having extensive first-pass metabolism and rapid elimination.

The effect of pH, buffer capacity and ionic strength on quetiapine fumarate release from matrix tablets prepared using two different polymeric blends.

The objective of this study was to investigate the effect of the different physiological parameters of the gastrointestinal (GI) fluid (pH, buffer capacity, and ionic strength) on the in vitro release of the weakly basic BCS class II drug quetiapine fumarate (QF) from two once-a-day matrix tablet formulations (F1 and F2) developed as potential generic equivalents to Seroquel® XR. F1 tablets were prepared using blends of high and low viscosity grades of hydroxypropyl methylcellulose (HPMC K4M and K100LV, respectively), while F2 tablets were prepared from HPMC K4M and PEGylated glyceryl behenate (Compritol® HD5 ATO). The two formulations attained release profiles of QF over 24 h similar to that of Seroquel® XR using the dissolution medium published by the Food and Drug Administration (FDA). A series of solubility and in vitro dissolution studies was then carried out using media that simulate the gastric and intestinal fluids and cover the physiological pH, buffer capacity and ionic strength range of the GIT. Solubility studies revealed that QF exhibits a typical weak base pH-dependent solubility profile and that the solubility of QF increases with increasing the buffer capacity and ionic strength of the media. The release profiles of QF from F1, F2 and Seroquel® XR tablets were found to be influenced by the pH, buffer capacity and ionic strength of the dissolution media to varying degrees. Results highlight the importance of studying the physiological variables along the GIT in designing controlled release formulations for more predictive in vitro-in vivo correlations.

The preclinical discovery and development of quetiapine for the treatment of mania and depression.

INTRODUCTION: Bipolar disorder is a chronic disabling condition characterized by alternating manic and depressive episodes. Bipolar disorder has been associated with functional impairment, poor quality of life, morbidity and mortality. Despite its significant clinical, social and economic burden, treatment options for bipolar disorder are still limited. Several clinical trials have shown efficacy of the atypical antipsychotic quetiapine (QTP) in the treatment of this condition. However, the mechanisms underlying the antidepressant and anti-manic effects of QTP remain poorly understood. Areas covered: The article provides the emerging evidence from pre-clinical studies regarding the antidepressant and anti-manic mechanisms of action of QTP. In combination with its primary active metabolite norquetiapine, QTP modulates several neurotransmitter systems, including serotonin, dopamine, noradrenaline and histamine. QTP also seems to influence mediators of the immune system. Expert opinion: Pre-clinical studies have provided valuable information on the potential antidepressant mechanisms of action of QTP, but pre-clinical studies on QTP's anti-manic effects are still scarce. A major problem refers to the lack of valid experimental models for bipolar disorder. Additionally, immune and genetic based studies are largely descriptive. The role of the QTP metabolite norquetiapine in modulating non-neurotransmitter systems also needs to be further addressed.

Quetiapine Nanoemulsion for Intranasal Drug Delivery: Evaluation of Brain-Targeting Efficiency.

To evaluate the possibility of improved drug delivery of quetiapine fumarate (QTP), a nanoemulsion system was developed for intranasal delivery. Effects of different HLBs of Emalex LWIS 10, PEG 400 and Transcutol P, as co-surfactants, were studied on isotropic region of pseudoternary-phase diagrams of nanoemulsion system composed of capmul MCM (CPM) as oil phase, Tween 80 as surfactant and water. Phase behaviour, globule size, transmission electron microscope (TEM) photographs and brain-targeting efficiency of quetiapine nanoemulsion were investigated. In vitro dissolution study of optimised nanoemulsion formulation, with mean diameter 144 ± 0.5 nm, showed more than twofold increase in drug release as compared with pure drug. According to results of in vivo tissue distribution study in Wistar rats, intranasal administration of QTP-loaded nanoemulsion had shorter T max compared with that of intravenous administration. Higher drug transport efficiency (DTE%) and direct nose-to-brain drug transport (DTP%) was achieved by nanoemulsion. The nanoemulsion system may be a promising strategy for brain-targeted delivery of QTP.

Comparative Physicochemical and Pharmacokinetic Properties of Quetiapine and Its Active Metabolite Norquetiapine.

Quetiapine (QTP) is an atypical antipsychotic drug commonly used to treat several psychiatric disorders and is metabolized into the active metabolite norquetiapine (NQTP). This study was designed to evaluate and compare the physicochemical properties, metabolic stability, brain distribution, and pharmacokinetics of QTP and NQTP. Compared to QTP, NQTP had a higher pKa, solubility, and rat liver microsomal stability, optimal log D and similar log P values. For pharmacokinetic evaluation, QTP and NQTP were administered orally and intravenously to rats at various doses. The plasma QTP and NQTP concentrations in rats were determined by a fully-validated liquid-chromatography tandem mass spectrometry (LC-MS/MS). Over the investigated dosing range, both QTP and NQTP showed linear pharmacokinetics. Following oral administration of the same dose, the area under the concentration-time curve (AUC0-∞) and maximum serum concentration (Cmax) were larger after NQTP administration compared to QTP administration. In addition, NQTP had a greater absolute oral bioavailability compared to QTP (15.6% vs. 0.63%, respectively). The brain-to-plasma concentration ratio was greater after NQTP administration compared to the QTP and NQTP ratios after QTP administration. NQTP administration results in increased systemic exposure and brain distribution compared to QTP administration. Future studies are needed to evaluate the pharmacologic and toxicologic effects of increased NQTP exposures.

Experimental and in silico assessment of fate and effects of the antipsychotic drug quetiapine and its bio- and phototransformation products in aquatic environments.

The antipsychotic drug quetiapine (QUT) has been frequently detected in sewage treatment plants. However, information on the fate of QUT in aquatic environments and its behavior during UV treatment is limited. In this study, QUT is shown not to be readily biodegradable in the Closed Bottle Test and the Manometric Respirometry Test according to OECD guidelines. The main biotransformation product (BTP) formed in the tests, a carboxylic acid derivative, was identified by means of high-resolution mass spectrometry. This BTP is presumably a human metabolite and showed higher detection rates than QUT in a river sampling campaign conducted in northern Germany. UV elimination kinetics of QUT at different initial concentrations (226.5, 45.3, 11.3, and 2.3 µmol L-1) were faster at lower initial concentrations. All seven phototransformation products (PTPs) could be still identified at initial concentration of 11.3 µmol L-1. The photolytic mixture generated after 128 min of photolysis of QUT was not better biodegradable than QUT. Initial UV treatment of QUT led to the formation of several additional BTPs. Four of them were identified. The bacterial cytotoxicity and genotoxicity before and after phototransformation of QUT in a modified luminescent bacteria test (LBT) and the umu-test (ISO/FDIS 13829) showed cytotoxic effects in the LBT for QUT. Furthermore, PTPs had similar cytotoxic effects on luminescent bacteria. The umu-test did not reveal any genotoxic activity for QUT or PTPs. In conclusion, the release of QUT into sewage treatment plants and aquatic environments could result in the formation of a main BTP. Additional UV treatment of QUT would lead to the formation of additional BTPs. Moreover, treatment did not result in lower toxicity to tested organisms. In conclusion, UV treatment of QUT should be considered critically as a potential treatment for QUT in aquatic systems.

Development of a Physiologically Based Pharmacokinetic/Pharmacodynamic Model to Predict the Impact of Genetic Polymorphisms on the Pharmacokinetics and Pharmacodynamics Represented by Receptor/Transporter Occupancy of Central Nervous System Drugs.

BACKGROUND: Genetic polymorphisms are major determinants of individual variability in a drug's efficacy and safety, which is one of the main challenges in current clinical practice and drug development. The aim of this work was to develop a physiologically based pharmacokinetic (PBPK)/pharmacodynamic (PD) model to predict changes in the PK parameters associated with genetic polymorphisms and the impact of these changes on drugs' PD effect. METHODS: We developed PBPK models for two central nervous system (CNS) medications, namely quetiapine and fluvoxamine that are substrates for polymorphic enzymes by incorporating the corresponding alterations in the enzyme activity and/or abundance. Then, the PBPK models were linked to PD models to predict the influence of these changes on the drugs' PD effect. RESULTS: Application of the PBPK models for prediction of phenotypic differences in the PKs compared favorably with reported clinical data. In addition, the PBPK/PD models were able to describe the relationship between the drugs' PD effect and their unbound fractions in the brain and predict changes in receptor/transporter occupancy percentages, obtained from positron emission tomography occupancy studies, associated with genetic variations. CONCLUSIONS: This work provides a simplified approach to predict the influence of genetic polymorphisms on the PK parameters and associated PD effect for CNS drugs. The impact of these polymorphisms on the drugs' PD requires further in vivo validation.