RESUMEN
Altered cytochromes P450 enzymes (CYP) and P-glycoprotein transporter (P-gp) activity may explain variabilities in drug response. In this study, we analyzed four years of phenotypic assessments of CYP/P-gp activities to optimize pharmacotherapy in psychiatry. A low-dose probe cocktail was administered to evaluate CYP1A2, 2B6, 2D6, 2C9, 2C19, 3A4, and P-gp activities using the probe/metabolite concentration ratio in blood or the AUC. A therapeutic adjustment was suggested depending on the phenotyping results. From January 2017 to June 2021, we performed 32 phenotypings, 10 for adverse drug reaction, 6 for non-response, and 16 for both reasons. Depending on the CYP/P-gp evaluated, only 23% to 56% of patients had normal activity. Activity was decreased in up to 57% and increased in up to 60% of cases, depending on the CYP/P-gp evaluated. In 11/32 cases (34%), the therapeutic problem was attributable to the patient's metabolic profile. In 10/32 cases (31%), phenotyping excluded the metabolic profile as the cause of the therapeutic problem. For all ten individuals for which we had follow-up information, phenotyping allowed us to clearly state or clearly exclude the metabolic profile as a possible cause of therapeutic failure. Among them, seven showed a clinical improvement after dosage adaptation, or drug or pharmacological class switching. Our study confirmed the interest of CYP and P-gp phenotyping for therapeutic optimization in psychiatry.
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High mobility group box 1 (HMGB1) is a pro-inflammatory cytokine that emerges as a promising peripheral marker of inflammation. HMGB1 and C-reactive protein levels were assessed in plasma of control subjects and remitted patients with bipolar disorder (BD). HMGB1 levels were significantly higher in patients with BD as compared to control subjects whereas C-reactive protein levels did not differ between the two groups. No significant effect of potential covariates was identified. The results of this pilot study suggest that HMGB1 might be a specific peripheral marker of inflammation in BD.
Asunto(s)
Trastorno Bipolar/sangre , Trastorno Bipolar/diagnóstico , Proteína HMGB1/sangre , Adolescente , Adulto , Biomarcadores/sangre , Trastorno Bipolar/psicología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proyectos Piloto , Adulto JovenRESUMEN
BACKGROUND: Better knowledge of opioid pharmacology after Roux-en-Y gastric bypass (RYGB) is required for optimizing their use in this growing population. OBJECTIVE: The aim of this case-controlled pharmacokinetic (PK) study was to compare morphine and its glucuronidated metabolites (morphine-3-glucuronide and morphine-6-glucuronide) plasma PKs between patients with RYGB and their controls. SETTINGS: University hospital, Lariboisière Hospital, Paris. METHODS: Thirty milligrams of morphine as a sustained-release formulation was orally administered in 12 women who had undergone RYGB for at least 2 years (RYGB group) and in their nonsurgical controls matched for sex, body mass index (±2 points), and age (±5 yr). Morphine, morphine-3-glucuronide, and morphine-6-glucuronide plasma concentrations over a 12-hour period were determined by a validated method using liquid chromatography mass spectrometry in tandem. Drowsiness, respiratory rate, and oxygen saturation were monitored during the PK visit. RESULTS: Morphine oral area under the curve (for time 0-12 hr; 115.8 ± 108.0 nmol.hr/L and 86.9 ± 38.8 nmol.hr/L for RYGB group and control group, respectively, P = .71), morphine at maximal concentration, metabolites oral area under the curve (for time 0-12 hr), and other PK parameters were similar between groups. After drug administration, mean drowsiness was superior in RYGB group. Mean respiratory rate and oxygen saturation were similar in both groups. CONCLUSION: No dose adjustment seems to be needed for sustained release morphine when prescribed to RYGB patients.
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Derivación Gástrica , Derivados de la Morfina/sangre , Morfina/farmacocinética , Obesidad Mórbida/cirugía , Dolor Postoperatorio/prevención & control , Administración Oral , Adolescente , Adulto , Anciano , Analgésicos Opioides/administración & dosificación , Analgésicos Opioides/farmacocinética , Índice de Masa Corporal , Estudios de Casos y Controles , Cromatografía Liquida , Preparaciones de Acción Retardada , Relación Dosis-Respuesta a Droga , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Morfina/administración & dosificación , Obesidad Mórbida/sangre , Dolor Postoperatorio/sangre , Adulto JovenRESUMEN
The AhR is a cytosolic ligand-dependent transcription factor activated by both endogenous and exogenous chemicals. It can regulate expression of many target genes including some inflammatory cytokines and chemokines. To date AhR implication in the regulation of inflammatory cytokines and chemokines at human cerebral endothelium has not been addressed. In the present study, we investigated whether AhR could regulate the expression of two pro-inflammatory cytokines and one chemokine i.e. IL-1ß, IL-6 and IL-8 in the hCMEC/D3 human cerebral microvascular endothelial cell line. Exposure to TCDD increased IL-1ß mRNA expression levels in hCMEC/D3. By using small interfering RNA against AhR we demonstrated that TCDD effects on IL-1ß expression were mediated through AhR activation. Regarding IL-6 and IL-8, TCDD exposure had little or no effect on their mRNA levels in hCMEC/D3. In conclusion, our findings suggest that AhR-mediated IL-1ß regulation in cerebral endothelium could induce BBB breakdown and contribute to the pathogenesis of a variety of neurologic disorders.
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Células Endoteliales/efectos de los fármacos , Interleucina-1beta/genética , Dibenzodioxinas Policloradas/toxicidad , Receptores de Hidrocarburo de Aril/genética , Encéfalo/citología , Línea Celular , Células Endoteliales/metabolismo , Humanos , Interleucina-6/genética , Interleucina-8/genética , Microvasos/citología , ARN Mensajero/metabolismo , ARN Interferente Pequeño/genéticaRESUMEN
Bipolar disorder (BD) is a long-recognized severe and common psychiatric disorder, with a complex and often diverse range of presentations. BD is a heterogenous disorder that has traditionally, if rather simply, been defined by the recurrences of manic and depressive episodes, and presents with numerous immune-inflammatory and circadian/sleep abnormalities. A number of different lines of research have investigated the biological underpinnings of BD and demonstrate a heritability of about 80-90%. This genetic contribution is thought to be mediated by a wide array of genetic factors, rather than being strongly influenced by a couple of genes. In this context, a clearer formulation of the biological underpinnings of BD is needed in order to encompass the diverse effects of multiple susceptibility genes. The biological underpinnings of BD includes work that has focussed on the role played by increased immune inflammatory activity, particularly changes in pro-inflammatory cytokines, as measured both centrally and systemically. Changes in immune- inflammatory activity are intimately associated with alterations in levels of oxidative and nitrosative stress (O&NS), which are increased in BD. Many of the neuroregulatory changes driven by O&NS and immune-inflammatory activity are mediated by the tryptophan catabolite (TRYCAT) pathways, with changes in TRYCATs being evident both centrally and peripherally. A consequence of increased pro-inflammatory cytokines, is their induction of indoleamine 2,3-dioxygenase (IDO), which takes tryptophan away from serotonin, Nacetylserotonin and melatonin synthesis, driving it to the synthesis of neuroregulatory TRYCATs. Most work exploring such changes has emphasized the role of TRYCATs in enhancing or decreasing neuronal activity. However, a relatively overlooked consequence of cytokine induced IDO and TRYCAT pathway activation is the impact that this has on aryl hydrocarbon receptor (AhR) activation and in decreasing melatonergic pathway activity. Melatonin is classically associated with night-time synthesis by the pineal gland, in turn regulating circadian rhythms. However, melatonin is produced by many, if not all mitochondria containing cells, with consequences for gut regulation, as well as glia and immune cell reactivity. The melatonergic pathways are genetic susceptibility factors for BD. Interactive changes in O&NS, immune-inflammatory activity, TRYCATs and the melatonergic pathways form an emerging biological perspective on the etiology, course and management of BD. Here, we review such changes in BD, and how this better integrates the diverse array of BD presentations and comorbidities, including addiction and cardiovascular disorders as well as decreased life-expectancy. We then look at the future directions such research may take.
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Trastorno Bipolar/fisiopatología , Quinurenina/metabolismo , Melatonina/metabolismo , Transducción de Señal , Triptófano/metabolismo , Animales , HumanosRESUMEN
The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor activated by a variety of widespread persistent environmental pollutants such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). It can transactivate the expression of several target genes. Recently AhR transcripts were detected in isolated human brain microvessels and in the hCMEC/D3 human cerebral microvascular endothelial cell line, an in vitro model of the human cerebral endothelium. To date AhR implication in the co-regulation of ABCB1, ABCG2 and CYP1B1 at human cerebral endothelium has not been addressed. Here we investigated whether AhR could co-regulate ABCB1, ABCG2 and CYP1B1 expressions in the hCMEC/D3 cell line. Exposure to TCDD induced a concentration-dependent increase in CYP1B1 expression. We demonstrated AhR involvement in the TCDD-mediated increase in CYP1B1 expression by using small interfering RNA against AhR. Western blotting analysis also revealed an increase in CYP1B1 protein expression following TCDD exposure in hCMEC/D3. Regarding ABCB1 and ABCG2, exposure to TCDD had no effect on their protein expressions and functional activities. In conclusion our data indicated a differential modulation of CYP1B1 and ABCB1/ABCG2 expressions in hCMEC/D3 cells following TCDD exposure.
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Transportadoras de Casetes de Unión a ATP/metabolismo , Corteza Cerebral/irrigación sanguínea , Corteza Cerebral/efectos de los fármacos , Citocromo P-450 CYP1B1/metabolismo , Proteínas de Neoplasias/metabolismo , Dibenzodioxinas Policloradas/toxicidad , Receptores de Hidrocarburo de Aril/metabolismo , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2 , Línea Celular , Corteza Cerebral/metabolismo , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Humanos , Microvasos/efectos de los fármacos , Transducción de Señal/efectos de los fármacosRESUMEN
The expression of aryl hydrocarbon receptor (AhR) transcription factor was detected at transcript level in freshly isolated human brain microvessels and in the hCMEC/D3 human cerebral microvascular endothelial cell line. Recent studies have demonstrated that AhR pathway is able to crosstalk with other pathways such as hypoxia signaling pathway. Therefore, we used the hCMEC/D3 cell line to investigate the potential crosstalk between AhR and hypoxia signaling pathways. First, we performed two different hypoxia-like procedures in hCMEC/D3 cells; namely, exposition of cells to 150 µM deferoxamine or to glucose and oxygen deprivation for 6 h. These two procedures led to hypoxia-inducible factor (HIF)-1α and HIF-2α proteins accumulation together with a significant induction of the two well-known hypoxia-inducible genes VEGF and GLUT-1. Both HIF-1α and -2α functionally mediated hypoxia response in the hCMEC/D3 cells. Then, we observed that a 6 h exposure to 25 nM 2,3,7,8-tetrachlorodibenzo-p-dioxin, a strong AhR ligand, up-regulated CYP1A1 and CYP1B1 expression, and that this effect was AhR dependent. Regarding AhR and hypoxia crosstalk, our experiments revealed that an asymmetric interference between these two pathways effectively occurred in hCMEC/D3 cells: hypoxia pathway interfered with AhR signaling but not the other way around. We studied the putative crosstalk of AhR and hypoxia pathways in hCMEC/D3 human cerebral microvascular endothelial cells. While hypoxia decreased the expression of the two AhR target genes CYP1A1 and CYP1B1, AhR activation results in no change in hypoxia target gene expression. This is the first sign of AhR and hypoxia pathway crosstalk in an in vitro model of the human cerebral endothelium.
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Circulación Cerebrovascular/fisiología , Células Endoteliales/metabolismo , Microvasos/metabolismo , Receptores de Hidrocarburo de Aril/metabolismo , Hipoxia de la Célula/fisiología , Células Cultivadas , Humanos , Microvasos/citología , Datos de Secuencia MolecularRESUMEN
Since the discovery of P-glycoprotein (P-gp) in brain microvessels composing the human blood-brain barrier (BBB), ATP-binding cassette (ABC) transporters have been recognized as bottlenecks in the development and delivery of neuropharmaceuticals. ABC transporters are expressed predominately at the plasma luminal membrane of brain capillary endothelial cells. These ABC transporters are responsible for the efflux of their substrates from the endothelial cells to the bloodstream against the concentration gradient and thus limit the entry of some drugs within the central nervous system (CNS). Advanced quantitative molecular biology tools allowed gene and protein quantification of the components of microvessels isolated from different species including human. Recently, positron emission tomography using radiolabelled probes that are substrates of ABC transporters allowed the determination of their functional activity at the human BBB. Here, we summarized new information regarding the relative expression, substrate recognition pattern for CNS drugs and functional activity of ABC transporters that are quantitatively expressed at the human BBB.
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Transportadoras de Casetes de Unión a ATP/metabolismo , Barrera Hematoencefálica/metabolismo , Sistema Nervioso Central/metabolismo , Sistemas de Liberación de Medicamentos , Preparaciones Farmacéuticas/administración & dosificación , Animales , Barrera Hematoencefálica/efectos de los fármacos , Sistema Nervioso Central/efectos de los fármacos , HumanosRESUMEN
Knockout (KO) animals are useful tools with which to assess the interplay between P-glycoprotein (P-gp; Abcb1) and the breast cancer resistance protein (Bcrp, Abcg2), two major ABC-transporters expressed at the blood-brain barrier (BBB). However, one major drawback of such deficient models is the possible involvement of compensation between transporters. In the present study, P-gp and Bcrp distribution in the brain as well as P-gp expression levels at the BBB were compared between the Bcrp TGEM KO rat model and the wild-type (WT) strain. Therefore, we used confocal microscopy of brain slices and western blot analysis of the isolated brain microvessels forming the BBB. This deficient rat model was used to assess the influence of Bcrp on the brain and peripheral kinetics of its substrate [(11)C]befloxatone using positron emission tomography (PET). The influence of additional P-gp inhibition was tested using elacridar (GF120918) 2 mg/kg in Bcrp KO rats. The distribution pattern of P-gp in the brain as well as P-gp expression levels at the BBB was similar in Bcrp-deficient and WT rats. Brain and peripheral kinetics of [(11)C]befloxatone were not influenced by the lack of Bcrp. Neither was the brain uptake of [(11)C]befloxatone in Bcrp-deficient rats influenced by the inhibition of P-gp. In conclusion, the Bcrp-deficient rat strain, in which we detected no compensatory mechanism or modification of P-gp expression as compared to WT rats, is a suitable model to study Bcrp function separately from that of P-gp at the BBB. However, although selectively transported by BCRP in vitro, our results suggest that [(11)C]befloxatone PET imaging might not be biased by impaired function of this transporter in vivo.
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Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Transportadoras de Casetes de Unión a ATP/metabolismo , Encéfalo/metabolismo , Oxazoles/farmacología , Ratas Transgénicas/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2 , Transportadoras de Casetes de Unión a ATP/genética , Animales , Masculino , Tomografía de Emisión de Positrones , Ratas , Ratas WistarRESUMEN
Since its discovery at the beginning of the 20th century, the blood-brain barrier (BBB) has been considered for a long time as a "physical barrier" able to limit brain distribution of highly molecular weight and/or polar compounds. This early concept of an anatomical barrier between the blood and the brain was supported by the finding of unique tight junctions between the brain endothelial cells so that they formed a continuous wall preventing the paracellular diffusion of solutes. In the middle of the 50's, BBB has been proposed as a "biochemical barrier" able to control the supply of brain to essential nutriments. More recently, BBB was evidenced as a key element in controlling effects of central nervous system drugs, since it plays a critical role in the uptake and efflux of drugs from the blood to the brain, or vice versa, hence affecting their concentrations and effects in the central nervous system (CNS). The BBB has therefore been more recently defined as a "pharmacological barrier" since the endothelial cells were found to contain a range of metabolizing enzymes and transporters that control the rate and extent of drugs reaching the brain parenchyma via transcellular pathway. The emergence of new quantitative proteomic approaches allows quantifying these transporters and enzymes at the BBB, opening the way to identify new drugs that may be targeted to the brain.
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Barrera Hematoencefálica/química , Sistema Enzimático del Citocromo P-450/análisis , Células Endoteliales/química , Proteínas de Transporte de Membrana/análisis , Proteómica/tendencias , Barrera Hematoencefálica/enzimología , Barrera Hematoencefálica/fisiología , Encéfalo/metabolismo , Fármacos del Sistema Nervioso Central/metabolismo , Células Endoteliales/enzimología , HumanosRESUMEN
BACKGROUND: AhR activates the transcription of several target genes including CYP1B1. Recently, we showed CYP1B1 as the major cytochrome P450 (CYP) enzyme expressed in human brain microvessels. Here, we studied the effect of AhR activation by environmental pollutants on the expression of Cyp1b1 in rat brain microvessels. METHODS: Expression of AhR and Cyp1b1 was detected in isolated rat brain microvessels. AhR was immunovisualised in brain microvessel endothelial cells. The effect of AhR ligands on Cyp1b1 expression was studied using isolated brain microvessels after ex vivo and/or in vivo exposure to TCDD, heavy hydrocarbons containing diesel exhaust particles (DEP) or Δ9-tetrahydrocannabinol (Δ9-THC). RESULTS: After ex vivo exposure to TCDD (a highly potent AhR ligand) for 3 h, Cyp1b1 expression was significantly increased by 2.3-fold in brain microvessels. A single i.p. dose of TCDD also increased Cyp1b1 transcripts (22-fold) and Cyp1b1 protein (2-fold) in rat brain microvessels at 72 h after TCDD. Likewise, DEP treatment (in vivo and ex vivo) strongly induced Cyp1b1 protein in brain microvessels. DEP-mediated Cyp1b1 induction was inhibited by actinomycin D, cycloheximide, or by an AhR antagonist. In contrast, a sub-chronic in vivo treatment with Δ9-THC once daily for 7 seven days had no effect on Cyp1b1 expression CONCLUSIONS: Our results show that TCDD and DEP strongly induced Cyp1b1 in rat brain microvessels, likely through AhR activation.
RESUMEN
The recent identification of drug-metabolizing enzymes cytochrome P450 (CYP) in the human blood-brain barrier (BBB) raises the question of whether these enzymes act in concert with ATP-binding cassette (ABC) transporters to limit the brain distributions of drugs. We recently demonstrated several CYP genes in freshly isolated human brain microvessels; the main isoforms expressed were CYP1B1 and CYP2U1. Many studies using different experimental approaches have revealed that P-glycoprotein (P-gp, ABCB1), breast cancer resistance protein (BCRP, ABCG2) and the multidrug resistance-associated protein 4 (MRP4, ABCC4) are the main ABC transporters in the human BBB. The first part of this review covers recent studies on the expression, regulation and function of CYP450 and ABC transporters in the rodent and human BBBs. The second part focuses on the possible interplay between some CYPs and certain ABC transporters at the BBB, which makes it a determining element of brain drug concentrations and thus of the effects of centrally acting drugs.
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Transportadoras de Casetes de Unión a ATP/metabolismo , Barrera Hematoencefálica/metabolismo , Sistema Enzimático del Citocromo P-450/metabolismo , Animales , Encéfalo , Humanos , Microvasos/metabolismo , Preparaciones Farmacéuticas/metabolismo , Roedores , Distribución TisularRESUMEN
We have investigated the transcriptomic and/or proteomic patterns of 71 solute carrier (SLC) and organic solute (OST) transporters, 34 ATP-binding cassette (ABC) transporters, and 51 metabolizing enzymes in human brain microvessels. We used quantitative RT-PCR and LC-MS/MS to examine isolated brain microvessels and cortex biopsies from 12 patients with epilepsia or glioma. SLC2A1/GLUT1, SLC1A3/EAAT1, and SLC1A2/EAAT2 were the main SLC proteins whereas ABCG2/BCRP, ABCB1/MDR1, ABCA2 and ABCA8 were the main ABC quantified in isolated brain microvessels; ABCG2/BCRP was 1.6-fold more expressed than ABCB1/MDR1, and ABCC4/MRP4 was 10 times less abundant than ABCB1/MDR1. CYP1B1 and CYP2U1 were the only quantifiable CYPs. Finally, GSTP1, COMT, GSTM3, GSTO1 and GSTM2 proteins were the main phase II enzymes quantified; UGTs and NATs were not detected. Our extensive investigation of gene and protein patterns of transporters and metabolizing enzymes provides new molecular information for understanding drug entry and metabolism in the human blood-brain barrier.
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Encéfalo/irrigación sanguínea , Encéfalo/metabolismo , Microvasos/metabolismo , Proteómica/métodos , Subfamilia B de Transportador de Casetes de Unión a ATP , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2 , Transportadoras de Casetes de Unión a ATP/genética , Transportadoras de Casetes de Unión a ATP/metabolismo , Cromatografía Liquida , Transportador 1 de Aminoácidos Excitadores/genética , Transportador 1 de Aminoácidos Excitadores/metabolismo , Transportador 2 de Aminoácidos Excitadores , Transportador de Glucosa de Tipo 1/genética , Transportador de Glucosa de Tipo 1/metabolismo , Proteínas de Transporte de Glutamato en la Membrana Plasmática/genética , Proteínas de Transporte de Glutamato en la Membrana Plasmática/metabolismo , Gutatión-S-Transferasa pi/genética , Gutatión-S-Transferasa pi/metabolismo , Glutatión Transferasa/genética , Glutatión Transferasa/metabolismo , Humanos , Técnicas In Vitro , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Espectrometría de Masas en Tándem , Transcriptoma/genética , Transcriptoma/fisiologíaAsunto(s)
Antineoplásicos/economía , Composición de Medicamentos/economía , Servicio de Farmacia en Hospital/economía , Servicio de Farmacia en Hospital/legislación & jurisprudencia , Antineoplásicos/administración & dosificación , Costos y Análisis de Costo , Composición de Medicamentos/normas , Francia , Humanos , Servicio de Farmacia en Hospital/normasRESUMEN
IMPORTANCE OF THE FIELD: The identification of xenobiotic metabolizing enzymes (i.e., CYP) and transporters (i.e., ABC transporters) (XMET) in the human brain, including the BBB, raises the question whether these transporters and enzymes have specific functions in brain physiology, neuropharmacology and toxicology. AREAS COVERED IN THIS REVIEW: Relevant literature was identified using PubMed search articles published up to March 2010. Search terms included 'ABC transporters and P450 or CYP', 'drug metabolism, effect and toxicity' and 'neurodegenerative disease (Alzheimer and Parkinson diseases)' restricted to the field of 'brain or human brain'. WHAT THE READER WILL GAIN: This review aims to provide a better understanding of XMET functions in the human brain and show their pharmacological importance for improving drug delivery and efficacy and also for managing their side effects. Finally, the impact of brain XMET activity during neurodegenerative processes is discussed, giving an opportunity to identify new markers of human brain diseases. TAKE HOME MESSAGE: During the last 2 decades, much evidence concerning the specific distribution patterns of XMET, their induction by xenobiotics and endobiotics and their genetic variations have made cerebral ABC transporters and CYP enzymes key elements in the way individual patients respond to centrally acting drugs.
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Transportadoras de Casetes de Unión a ATP/metabolismo , Sistema Enzimático del Citocromo P-450/metabolismo , Xenobióticos/farmacocinética , Animales , Barrera Hematoencefálica/metabolismo , Encéfalo/enzimología , Encéfalo/metabolismo , Sistemas de Liberación de Medicamentos , Humanos , Enfermedades Neurodegenerativas/tratamiento farmacológico , Enfermedades Neurodegenerativas/fisiopatología , Xenobióticos/efectos adversosRESUMEN
We describe a 38-year-old smoking woman suffering from schizophrenia, hemodialysed 3 times a week, and treated with clozapine. Therapeutic drug monitoring of clozapine was performed to guide therapy.