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1. Case report : quantification of methadone-induced respiratory depression using toxicokinetic/toxicodynamic relationships

Author

Mégarbane, Bruno, Decleves, Xavier, Bloch, Vanessa, Bardin, Christophe, Chast, Francois, Baud, Frederic, Mégarbane, Bruno, Neuropsychopharmacologie des addictions. Vulnérabilité et variabilité expérimentale et clinique (NAVVEC - UM 81 (UMR 8206/ U705)), Université Paris Diderot - Paris 7 (UPD7)-Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Réanimation Médicale et Toxicologique [Hôpital Lariboisière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Hôpital Hôtel-Dieu [Paris]

Subjects
[SDV.TOX] Life Sciences [q-bio]/Toxicology, [SDV.MHEP.ME] Life Sciences [q-bio]/Human health and pathology/Emerging diseases, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.TOX]Life Sciences [q-bio]/Toxicology, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system
Abstract

International audience; Introduction: Methadone, the most widely delivered maintenance therapy for heroin addicts, may be responsible for life-threatening poisonings with respiratory depression. The toxicokinetics and the toxicokinetic/toxicodynamic (TK/TD) relationships of methadone enantiomers have been poorly investigated in acute poisonings. The aim of this study was to describe the relationships between methadone-related respiratory effects and their corresponding concentrations.Methods: We report a 44-year-old methadone-maintained patient who ingested a 240-mg dose of methadone. He was found comatose with pinpoint pupils and respiratory depression. He was successfully treated with intravenous naloxone infusion over the course of 31 hours at a rate adapted to maintain normal consciousness and respiratory rate. We performed a TK/TD analysis of the naloxone infusion rate needed to maintain his respiratory rate at more than 12 breaths per minute (as toxicodynamics parameter) versus plasma R,S- and R-methadone concentrations (as toxicokinetics parameter), determined using an enantioselective high-performance liquid chromatography assay.Results: Initial plasma R,S-methadone concentration was 1,204 ng/ml. Decrease in plasma R- and S-methadone concentrations was linear and demonstrated a first-order pharmacokinetics (maximal observed concentrations 566 and 637 ng/ml, half-lives 16.1 and 13.2 hours, respectively). TK/TD correlation between naloxone infusion rate and R,S- and R-methadone concentrations fitted well a sigmoidal Emax model (concentration associated with a half-maximum effect [EC50] 334 and 173 ng/ml, Hill coefficient 10.0 and 7.8, respectively). In our chronically treated patient, EC50 values were in the range of previously reported values regarding methadone analgesic effects, suggesting that plasma methadone concentrations to prevent withdrawal are lower than those associated with methadone analgesic effects.Conclusion: After the ingestion of a toxic dose of a racemic mixture, plasma R- and S-enantiomer concentrations decreased in parallel. Despite large inter-individual variability in methadone toxicokinetics and toxicodynamics, TK/TD relationships would be helpful for providing quantitative data regarding the respiratory response to methadone in poisonings. However, further confirmatory TK/TD data are needed.

Published
2007
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3. Opioids and the Blood-Brain Barrier: A Dynamic Interaction with Consequences on Drug Disposition in Brain

Author

Salvatore Cisternino, Xavier Declèves, Catarina Chaves, Fernando Remião, Variabilité de réponse aux Psychotropes (VariaPsy - U1144), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Requimte, Universidade do Porto = University of Porto-Departamento de Química (DQ), Faculdade de Ciências e Tecnologia = School of Science & Technology (FCT NOVA), Universidade Nova de Lisboa = NOVA University Lisbon (NOVA)-Universidade Nova de Lisboa = NOVA University Lisbon (NOVA)-Faculdade de Ciências e Tecnologia = School of Science & Technology (FCT NOVA), Universidade Nova de Lisboa = NOVA University Lisbon (NOVA)-Universidade Nova de Lisboa = NOVA University Lisbon (NOVA), and Decleves, Xavier

Subjects
0301 basic medicine, opioids, Abcg2, [SDV]Life Sciences [q-bio], ATP-binding cassette transporter, Pharmacology, P-glycoprotein, Article, neuroinflammation, 03 medical and health sciences, 0302 clinical medicine, Medicine, Animals, Humans, Pharmacology (medical), TLR4, Neuroinflammation, biology, business.industry, Brain, Biological Transport, General Medicine, 3. Good health, Solute carrier family, [SDV] Life Sciences [q-bio], Analgesics, Opioid, Psychiatry and Mental health, 030104 developmental biology, Neurology, Opioid, ABC transporters, Nonlinear Dynamics, Blood-Brain Barrier, biology.protein, ATP-Binding Cassette Transporters, Neurology (clinical), Efflux, business, 030217 neurology & neurosurgery, medicine.drug
Abstract

International audience; Background: Opioids are widely used in pain management, acting via opioid receptors and/or Toll-like receptors (TLR) present at the central nervous system (CNS). At the blood-brain barrier (BBB), several influx and efflux transporters, such as the ATP-binding cassette (ABC) P-glycoprotein (P-gp, ABCB1), Breast Cancer Resistance Protein (BCRP, ABCG2) and multidrug resistance-associated proteins (MRP, ABCC) transporters, and solute carrier transporters (SLC), are responsible for the transport of xenobiotics from the brain into the bloodstream or vice versa.Objective: ABC transporters export several clinically employed opioids, altering their neuropharmacokinetics and CNS effects. In this review, we explore the interactions between opioids and ABC transporters, and decipher the molecular mechanisms by which opioids can modify their expression at the BBB.Results: P-gp is largely implicated in the brain-to-blood efflux of opioids, namely morphine and oxycodone. Long-term exposure to morphine and oxycodone has proven to up-regulate the expression of ABC transporters, such as P-gp, BCRP and MRPs, at the BBB, which may lead to increased tolerance to the antinociceptive effects of such drugs. Recent studies uncover two mechanisms by which morphine may up-regulate P-gp and BCRP at the BBB: 1) via a glutamate, NMDA-receptor and COX-2 signaling cascade, and 2) via TLR4 activation, subsequent development of neuroinflammation, and activation of NF-kB, presumably via glial cells.Conclusion: The BBB-opioid interaction can culminate in bilateral consequences, since ABC transporters condition the brain disposition of opioids, while opioids also affect the expression of ABC transporters at the BBB, which may result in increased CNS drug pharmacoresistance.

Published
2017
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4. Imaging Probes and Modalities for the Study of Solute Carrier O (SLCO)-Transport Function In Vivo

Author

Xavier Declèves, Solène Marie, Salvatore Cisternino, Nicolas Tournier, Irène Buvat, Imagerie Moléculaire in Vivo (IMIV - U1023 - ERL9218), Service Hospitalier Frédéric Joliot (SHFJ), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Faculté de Pharmacie [Châtenay-Malabry], Université Paris-Sud 11 - Faculté de médecine (UP11 UFR Médecine)-Université Paris-Saclay, Optimisation Thérapeutique en Neuropsychopharmacologie (VariaPsy - U1144), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7), Université Paris Descartes - Faculté de Pharmacie de Paris (UPD5 Pharmacie), Université Paris Descartes - Paris 5 (UPD5), ANR-16-CE17-0011,ISOTOPK,Imagerie fonctionnelle des transporteurs SLCO (Solute Carrier O) chez l'Homme : implication dans la variabilité d’élimination et de distribution tissulaire des médicaments(2016), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud - Paris 11 - Faculté de médecine (UP11 UFR Médecine), Université Paris-Sud - Paris 11 (UP11)-Université Paris-Sud - Paris 11 (UP11)-Université Paris-Saclay, Variabilité de réponse aux Psychotropes (VariaPsy - U1144), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Faculté de Pharmacie de Paris - Université Paris Descartes (UPD5 Pharmacie), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), ANR-16-CE17-0011,ISOTOPK,Imagerie fonctionnelle des transporteurs SLCO (Solute Carrier O) chez l'Homme : implication dans la variabilité d'élimination et de distribution tissulaire des médicaments(2016), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Saclay-Université Paris-Sud - Paris 11 - Faculté de médecine (UP11 UFR Médecine), Université Paris-Sud - Paris 11 (UP11)-Université Paris-Sud - Paris 11 (UP11), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), and Decleves, Xavier

Subjects
Pathology, medicine.medical_specialty, Solute transporters, [SDV]Life Sciences [q-bio], Organic Anion Transporters, Hepatic transport, Pharmaceutical Science, [SDV.IB.MN]Life Sciences [q-bio]/Bioengineering/Nuclear medicine, 030226 pharmacology & pharmacy, Substrate Specificity, solute transporters, 03 medical and health sciences, 0302 clinical medicine, Nuclear magnetic resonance, Organic anion-transporting polypeptide transporters, In vivo, [INFO.INFO-IM]Computer Science [cs]/Medical Imaging, medicine, Animals, Humans, Modalities, medicine.diagnostic_test, Drug disposition, Chemistry, Biological Transport, Magnetic resonance imaging, Imaging methods, 3. Good health, Solute carrier family, [SDV] Life Sciences [q-bio], Pharmaceutical Preparations, Positron emission tomography, 030220 oncology & carcinogenesis, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Indicators and Reagents, Emission computed tomography, Function (biology)
Abstract

International audience; Transporters of the Solute Carrier O (SLCO) family, former organic anion-transportingpolypeptides (OATP), are now recognized as key players in pharmacokinetics. Imagingis increasingly regarded as a relevant method to elucidate and decipher the intrinsicrole of SLCO in controlling drug disposition in plasma and tissues. Current research inthis representative field of translational research is based on different imagingmodalities including nuclear imaging, such as Single Photon Emission ComputedTomography (SPECT) or Positron Emission Tomography (PET), as well as MagneticResonance Imaging (MRI). Imaging modalities can be compared in terms of sensitivity,quantitative properties, spatial resolution, variety of ligands and radiation exposure. Allof these approaches rely on the use of SLCO-substrates that are detected usingcorresponding modalities. The present review aims at reporting and comparing theimaging probes that have been proposed to study SLCO-transport function, in termsof $in\ vitro$ specificity, $in\ vivo$ behavior and clinical validation.

Published
2017
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5. Diphenhydramine as a selective probe to study H+-antiporter function at the blood–brain barrier: Application to [11C]diphenhydramine positron emission tomography imaging

Author

Sébastien Goutal, Sylvain Auvity, Fabien Caillé, Benoit Hosten, Xavier Declèves, Maria Smirnova, Hélène Chapy, Salvatore Cisternino, Nicolas Tournier, Decleves, Xavier, Imagerie Moléculaire in Vivo (IMIV - U1023 - ERL9218), Service Hospitalier Frédéric Joliot (SHFJ), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Variabilité de réponse aux Psychotropes (VariaPsy - U1144), and Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
positron emission tomography, [SDV]Life Sciences [q-bio], Perfusion scanning, solute carrier, Pharmacology, blood–brain barrier, Blood–brain barrier, 030226 pharmacology & pharmacy, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Nuclear magnetic resonance, medicine, Brain positron emission tomography, Tetraethylammonium, medicine.diagnostic_test, Diphenhydramine, Biological transporter, Antagonist, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Neurology, chemistry, proton antiporter, Positron emission tomography, Neurology (clinical), Cardiology and Cardiovascular Medicine, 030217 neurology & neurosurgery, Histamine, medicine.drug
Abstract

Diphenhydramine, a sedative histamine H1-receptor (H1R) antagonist, was evaluated as a probe to measure drug/H+-antiporter function at the blood–brain barrier. In situ brain perfusion experiments in mice and rats showed that diphenhydramine transport at the blood–brain barrier was saturable, following Michaelis–Menten kinetics with a Km = 2.99 mM and Vmax = 179.5 nmol s−1 g−1. In the pharmacological plasma concentration range the carrier-mediated component accounted for 77% of diphenhydramine influx while passive diffusion accounted for only 23%. [14C]Diphenhydramine blood–brain barrier transport was proton and clonidine sensitive but was influenced by neither tetraethylammonium, a MATE1 (SLC47A1), and OCT/OCTN (SLC22A1-5) modulator, nor P-gp/Bcrp (ABCB1a/1b/ABCG2) deficiency. Brain and plasma kinetics of [11C]diphenhydramine were measured by positron emission tomography imaging in rats. [11C]Diphenhydramine kinetics in different brain regions were not influenced by displacement with 1 mg kg−1 unlabeled diphenhydramine, indicating the specificity of the brain positron emission tomography signal for blood–brain barrier transport activity over binding to any central nervous system target in vivo. [11C]Diphenhydramine radiometabolites were not detected in the brain 15 min after injection, allowing for the reliable calculation of [11C]diphenhydramine brain uptake clearance (Clup = 0.99 ± 0.18 mL min−1 cm−3). Diphenhydramine is a selective and specific H+-antiporter substrate. [11C]Diphenhydramine positron emission tomography imaging offers a reliable and noninvasive method to evaluate H+-antiporter function at the blood–brain barrier.

Published
2016
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6. Expression and function of Abcg4 in the mouse blood-brain barrier: role in restricting the brain entry of amyloid-β peptide

Author

Shailendra B. Patel, Sophie Nicolic, Anne-Laure Raveu, Matthew Wortman, Nathalie Prince, Fanchon Bourasset, Jean-Michel Scherrmann, Stéphanie Chasseigneaux, Murielle Lochus, Agnès Dodacki, Bruno Saubaméa, Xavier Declèves, Optimisation thérapeutique en Neuropsychopharmacologie (OPTeN (UMR_S_1144 / U1144)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), University of Cincinnati (UC), Chasseigneaux, Stephanie, Variabilité de réponse aux Psychotropes (VariaPsy - U1144), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Faculté de Pharmacie de Paris (UPD5 Pharmacie), Université Paris Descartes - Paris 5 (UPD5), Université Paris Diderot - Paris 7 (UPD7), and Decleves, Xavier

Subjects
Models, Molecular, 0301 basic medicine, Cell Membrane Permeability, Protein Conformation, [SDV]Life Sciences [q-bio], Fluorescent Antibody Technique, Gene Expression, lcsh:Medicine, Peptide, Plasma protein binding, Mice, chemistry.chemical_compound, 0302 clinical medicine, Desmosterol, lcsh:Science, Mice, Knockout, chemistry.chemical_classification, Multidisciplinary, biology, Brain, Transmembrane protein, Cell biology, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Blood-Brain Barrier, Gene Targeting, ABCG4, Protein Binding, ATP Binding Cassette Transporter, Subfamily G, Blood–brain barrier, Article, Capillary Permeability, Structure-Activity Relationship, 03 medical and health sciences, In vivo, medicine, Animals, Amyloid beta-Peptides, lcsh:R, In vitro, 030104 developmental biology, chemistry, Genetic Loci, Immunology, biology.protein, ATP-Binding Cassette Transporters, lcsh:Q, Protein Multimerization, Biomarkers, 030217 neurology & neurosurgery
Abstract

ABCG4 is an ATP-binding cassette transmembrane protein which has been shown, in vitro, to participate in the cellular efflux of desmosterol and amyloid-β peptide (Aβ). ABCG4 is highly expressed in the brain, but its localization and function at the blood-brain barrier (BBB) level remain unknown. We demonstrate by qRT-PCR and confocal imaging that mouse Abcg4 is expressed in the brain capillary endothelial cells. Modelling studies of the Abcg4 dimer suggested that desmosterol showed thermodynamically favorable binding at the putative sterol-binding site, and this was greater than for cholesterol. Additionally, unbiased docking also showed Aβ binding at this site. Using a novel Abcg4-deficient mouse model, we show that Abcg4 was able to export Aβ and desmosterol at the BBB level and these processes could be inhibited by probucol and L-thyroxine. Our assay also showed that desmosterol antagonized the export of Aβ, presumably as both bind at the sterol-binding site on Abcg4. We show for the first time that Abcg4 may function in vivo to export Aβ at the BBB, in a process that can be antagonized by its putative natural ligand, desmosterol (and possibly cholesterol).

Published
2017
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7. Effect of Long-term In Vitro Lithium Exposure on mRNA Levels of Claudin-3, CYP1A1, ABCG2 and GSTM3 Genes in the hCMEC/D3 Human Brain Endothelial Cell Line

Author

Luo Huilong, Xavier Declèves, Ramzi Shawahna, Kayathiri Ganeshamoorthy, Pierre-Olivier Couraud, Jean-Michel Scherrmann, Decleves, Xavier, Variabilité de réponse aux Psychotropes (VariaPsy - U1144), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), An-Najah National University, Institut Cochin (IC UM3 (UMR 8104 / U1016)), and Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, [SDV]Life Sciences [q-bio], Gene Expression, ATP-binding cassette transporter, Biology, Cell Line, 03 medical and health sciences, 0302 clinical medicine, Cytochrome P-450 CYP1A1, ATP Binding Cassette Transporter, Subfamily G, Member 2, Claudin-3, Humans, Pharmacology (medical), RNA, Messenger, Claudin, Glutathione Transferase, Pharmacology, Tight junction, Wnt signaling pathway, Cytochrome P450, Brain, Endothelial Cells, Transporter, Cell biology, Neoplasm Proteins, [SDV] Life Sciences [q-bio], Endothelial stem cell, 030104 developmental biology, Cell culture, biology.protein, Lithium Chloride, 030217 neurology & neurosurgery, Biomarkers
Abstract

International audience; Background and objectives: Lithium chloride (LiCl) has been shown to improve the tightness of brain endothelial cell monolayers in vitro by inhibition of the GSK-3β enzyme, activation of the Wnt/beta-catenin pathway and regulation of tight junction (TJ) protein expression. However, the effect of LiCl on the drug transporters and drug-metabolizing enzymes has not been addressed so far. The hCMEC/D3 cell line is a validated in vitro BBB model expressing transporters and drug-metabolizing enzymes (phase 1 and 2). The present study was conducted to compare the mRNAs levels corresponding to several BBB endothelial markers in hCMEC/D3 cells with and without incubation in LiCl.Methods: We used quantitative real-time polymerase chain reaction (qRT-PCR) to quantify the mRNA expression of 5 tight junction (TJ) proteins, 4 adhesion proteins, 5 solute carriers, 7 ATP-binding cassette (ABC) transporters, 8 cytochrome P450 (CYP) and 17 phase 2 conjugation enzymes in hCMEC/D3 cells with and without incubation in LiCl.Results: Our study showed that LiCl treatment for 6 days at a concentration of 10 mM induced the TJ protein claudin-3, the ABC transporter BCRP/ABCG2, the cytochrome P-450 CYP1A1 and the glutathione-S-transferase GSTM3, while the other selected markers were not significantly affected.Conclusions: Our findings provide new insights into the effects of lithium on some drug transporters and drug-metabolizing enzymes in the BBB that may have consequences in pharmacotherapy.

Published
2017
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8. The effect of morbid obesity on morphine glucuronidation

Author

Jean-Michel Scherrmann, Alexandra Rouquette, Joan Tordjman, Jean-François Bergmann, Célia Lloret-Linares, Laurence Labat, Christine Poitou, Jean-Luc Bouillot, Huilong Luo, Stéphane Mouly, Xavier Declèves, Variabilité de réponse aux Psychotropes (VariaPsy - U1144), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Hôtel-Dieu [Paris], Hôpital Cochin [AP-HP], Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Nutrition et obésités: approches systémiques (UMR-S 1269) (Nutriomics), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Service de Chirurgie Viscérale [CHU Ambroise paré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Ambroise Paré [AP-HP], and Decleves, Xavier

Subjects
Male, 0301 basic medicine, medicine.medical_specialty, Glucuronosyltransferase, [SDV]Life Sciences [q-bio], Gastric Bypass, Glucuronidation, Cmax, 030226 pharmacology & pharmacy, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Pharmacokinetics, Weight loss, Internal medicine, medicine, Humans, Obesity, Pharmacology, Bariatric surgery, Morphine Derivatives, biology, Triglyceride, Morphine, Chemistry, medicine.disease, Obesity, Morbid, [SDV] Life Sciences [q-bio], 030104 developmental biology, Endocrinology, Anesthesia, Steatohepatitis, biology.protein, Female, medicine.symptom, medicine.drug
Abstract

International audience; The purpose of the present work was to study the change in morphine metabolic ratio in obese subjects before and after Roux-en-Y Gastric Bypass (RYGB) and to identify clinical and/or biological factors associated with this change. The pharmacokinetics (PK) of oral morphine (30mg), morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) was performed in patients before (n=25; mean BMI=43.2 (35.4-61.9)kg/m2), 7-15days (n=16) and 6 months after RYGB (n=19; mean BMI=32.3 (25.4-46.0)kg/m2). Morphine Cmax and AUC0-inf were significantly increased and morphine Tmax significantly shortened at 6 months after RYGB compared with preoperative data, indicating an important increase in the rate and extent of morphine absorption. The morphine metabolic ratio 0-inf M3G+M6G/Morphine, decreased significantly from the preoperative to 6 months postoperative period with an average of -26% (range -74%; +21%; p=0.004), but not in the immediate post-operative period. The change in morphine metabolic ratio was associated with a change in BMI, fat mass in kg, and triglyceride levels (rho=0.5, p≤0.04). The degree of change in several markers of low-grade inflammation, or the level of liver steatosis and fibrosis before surgery, was not associated with the change in morphine metabolic ratios. Our findings indicate that RYGB-induced weight loss significantly decreases morphine metabolic ratio, arguing for an effect of morbid obesity on glucuronidation. With glucuronide exposure at 6 months similar to preoperative values, a higher morphine AUC0-inf should encourage reducing morphine dosage in patients undergoing RYGB and chronically receiving immediate-release oral morphine.

Published
2017
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9. Translation in astrocyte distal processes sets molecular heterogeneity at the gliovascular interface

Author

Alice Gilbert, Nicolas Adam, Noémie Mazaré, Fabrice Chrétien, Mathieu Bahin, Stéphanie Chasseigneaux, Martine Cohen-Salmon, Corinne Blugeon, Sandrine Perrin, Bruno Saubaméa, Jean-Louis Laplanche, Stéphane Le Crom, Xavier Declèves, Juliette Pouch, Anne-Cécile Boulay, Bertrand Ducos, Leïla Bastianelli, Auguste Genovesio, Decleves, Xavier, Organisation et montée en puissance d'une Infrastructure Nationale de Génomique - - France-Génomique2010 - ANR-10-INBS-0009 - INBS - VALID, Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris sciences et lettres (PSL), Variabilité de réponse aux Psychotropes (VariaPsy - U1144), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Faculté de Pharmacie de Paris (UPD5 Pharmacie), Université Paris Descartes - Paris 5 (UPD5), Plates-formes mutualisées du centre de recherche pharmaceutique de Paris (P-MIM - UMS 3612), Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Histopathologie humaine et Modèles animaux, Institut Pasteur [Paris] (IP), Centre Hospitalier Sainte Anne [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de biologie de l'ENS Paris (IBENS), Département de Biologie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), GenomiqueENS (Genomique ENS), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Département de Biologie - ENS Paris, Laboratoire de Physique Statistique de l'ENS (LPS), Fédération de recherche du Département de physique de l'Ecole Normale Supérieure - ENS Paris (FRDPENS), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Analyse des Données à Haut Débit en Génomique (ADHDG), Evolution Paris Seine, Université des Antilles et de la Guyane (UAG)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université des Antilles et de la Guyane (UAG)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot - Paris 7 (UPD7), Université Sorbonne Paris Cité (USPC), This work was supported by Fondation pour la Recherche Médicale (FRM), the Labex MemoLife, and Fondation Gueules Cassées. The Ecole normale supérieure genomic platform was supported by the France Génomique national infrastructure, funded as part of the 'Investissements d'Avenir' program managed by the Agence Nationale de la Recherche (contract ANR-10-INBS-09)., ANR-10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010), Plateforme Génomique de l'IBENS, Institut de biologie de l'ENS Paris (UMR 8197/1024) (IBENS), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université des Antilles et de la Guyane (UAG)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Nice Sophia Antipolis (... - 2019) (UNS), Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Optimisation thérapeutique en Neuropsychopharmacologie (OPTeN (UMR_S_1144 / U1144)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut de Recherche pour le Développement (IRD)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Faculté de Pharmacie de Paris - Université Paris Descartes (UPD5 Pharmacie), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Biologie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Biologie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université des Antilles et de la Guyane (UAG)-Université Pierre et Marie Curie - Paris 6 (UPMC)

Subjects
0301 basic medicine, [SDV]Life Sciences [q-bio], Bioinformatics, Biochemistry, Article, 03 medical and health sciences, symbols.namesake, astrocyte, local translation, 0302 clinical medicine, translating ribosome immunoprecipitation, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Genetics, Protein biosynthesis, medicine, Molecular Biology, mRNAs localization, Chemistry, Endoplasmic reticulum, Translation (biology), Cell Biology, Golgi apparatus, Translocon, endfeet, Cell biology, [SDV] Life Sciences [q-bio], 030104 developmental biology, medicine.anatomical_structure, Secretory protein, Membrane protein, symbols, gliovascular unit, 030217 neurology & neurosurgery, Astrocyte
Abstract

Astrocytes send out long processes that are terminated by endfeet at the vascular surface and regulate vascular functions as well as homeostasis at the vascular interface. To date, the astroglial mechanisms underlying these functions have been poorly addressed. Here we demonstrate that a subset of messenger RNAs is distributed in astrocyte endfeet. We identified, among this transcriptome, a pool of messenger RNAs bound to ribosomes, the endfeetome, that primarily encodes for secreted and membrane proteins. We detected nascent protein synthesis in astrocyte endfeet. Finally, we determined the presence of smooth and rough endoplasmic reticulum and the Golgi apparatus in astrocyte perivascular processes and endfeet, suggesting for local maturation of membrane and secreted proteins. These results demonstrate for the first time that protein synthesis occurs in astrocyte perivascular distal processes that may sustain their structural and functional polarization at the vascular interface.

Published
2017
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10. RYGB and Drug Disposition: How to Do Better? Analysis of Pharmacokinetic Studies and Recommendations for Clinical Practice

Author

Xavier Declèves, P Faucher, Lorry Hachon, Célia Lloret-Linares, Claire Carette, Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Variabilité de réponse aux Psychotropes (VariaPsy - U1144), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Cochin [AP-HP], Service de Nutrition [CHU Pitié-Salpétrière], Institut E3M [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), and Decleves, Xavier

Subjects
Drug, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, media_common.quotation_subject, [SDV]Life Sciences [q-bio], Population, Gastric Bypass, Administration, Oral, 030209 endocrinology & metabolism, 030226 pharmacology & pharmacy, Galenic formulation, Permeability, 03 medical and health sciences, 0302 clinical medicine, Pharmacokinetics, Medicine, Humans, Postoperative Period, Medical prescription, education, Intensive care medicine, media_common, Postoperative Care, education.field_of_study, Nutrition and Dietetics, medicine.diagnostic_test, Drug disposition, business.industry, Biopharmaceutics Classification System, Obesity, Morbid, [SDV] Life Sciences [q-bio], Intestinal Absorption, Pharmaceutical Preparations, Therapeutic drug monitoring, Anesthesia, Surgery, Drug Monitoring, business
Abstract

An important issue in the follow-up of patients with bariatric surgery remains to determine whether their therapeutic management should be different after surgery. In this article, we first reviewed all pharmacokinetic studies involving at least four subjects who underwent the Roux-en-Y gastric bypass (RYGB) bariatric surgery. Twenty-five publications were selected and, overall, 25 drugs were studied. Drug solubility and permeability parameters for each drug were defined using different parameters or classifications. Increased rates of oral drug absorption were predominantly observed. Conversely, drug exposure differed from one drug to another. Considering the galenic formulation and the Biopharmaceutics Classification System (BCS) class may help the prediction of oral drug exposure outcome after RYGB. We propose a strategy aiming to guide prescription and drug monitoring in patients with RYGB. But further research is clearly needed due to the unique characteristics of the bariatric population. Priority should be given to drugs that do not have clinical or biological surrogates for dose adaptation.

Published
2017
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11. Morphine and metabolites plasma levels after administration of sustained release morphine in Roux-en-Y gastric bypass subjects versus matched control subjects

Author

Aude Jacob, Célia Lloret-Linares, Christine Poitou, Lorry Hachon, Rafael Reis, Laurence Labat, Xavier Declèves, Decleves, Xavier, Variabilité de réponse aux Psychotropes (VariaPsy - U1144), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département Biologie du Médicament et Toxicologie [AP-HP - Hôpital Cochin Broca Hôtel Dieu] (HUPC), AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Nutrition et obésités: approches systémiques (UMR-S 1269) (Nutriomics), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Hôpital Lariboisière-Fernand-Widal [APHP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
Male, [SDV]Life Sciences [q-bio], Administration, Oral, 030226 pharmacology & pharmacy, Body Mass Index, 0302 clinical medicine, Medicine, Oxygen saturation (medicine), Pain, Postoperative, education.field_of_study, Morphine, Area under the curve, Middle Aged, Obesity, Morbid, Analgesics, Opioid, [SDV] Life Sciences [q-bio], Anesthesia, Female, medicine.drug, Adult, medicine.medical_specialty, Adolescent, Respiratory rate, Metabolic ratio, Population, Gastric Bypass, 030209 endocrinology & metabolism, Pain, Young Adult, 03 medical and health sciences, Glucuronides, Pharmacokinetics, Humans, Obesity, education, Aged, Bariatric surgery, Morphine Derivatives, Dose-Response Relationship, Drug, business.industry, nutritional and metabolic diseases, Surgery, Opioids, Opioid, Case-Control Studies, Delayed-Action Preparations, business, Body mass index, Chromatography, Liquid, Follow-Up Studies
Abstract

International audience; 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.

Published
2017
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