Abstract
The anti-N-methyl-D-aspartate (NMDA) effect of dextromethorphan (DEM) seems to be mainly related to the unchanged drug rather than to its more potent metabolite dextrorphan (DOR). The aim of our study was to assess the involvement of P-glycoprotein (Pgp) and pH conditions in the transmembranal transport of these two NMDA antagonists, using a human in vitro Caco-2 cell monolayer model. Transmission electron microscopy, transepithelial electrical resistance, [3H]-mannitol permeability, Western blot analysis and the bidirectional transport of the positive controls, rhodamine and digoxine were used to confirm models integrity and validity. The bidirectional transport of DEM and DOR (1 to 100μM) across the monolayers was investigated in the presence and absence of the P-gp inhibitor cyclosporine A (10μM) at two pH conditions (pH 6.8/7.7-pH 7.4/7.4) and assessed with the specific and more potent P-gp inhibitor GF120918 (4μM). Analytical quantification was achieved using high performance liquid chromatography. At a pH gradient, DEM and DOR were subject to a significant active efflux transport (Papp(B-A) > 2-3x Papp(A-B); p < 0.01). However, neither the influx nor the efflux was affected by P-gp inhibitors. At physiological pH, we observed no more efflux of the drugs and no influence of the inhibitors. In conclusion, dextromethorphan and dextrorphan are not P-gp substrates. However, pH-mediated efflux mechanisms seem to be involved in limiting DEM gastrointestinal absorption. The preferential anti-NMDA central effect of DEM appears to be P-gp independent.
Keywords: P-glycoprotein, Caco-2 cells, Transport, Dextromethorphan, Dextrorphan
Current Drug Metabolism
Title: Lack of Interaction of the NMDA Receptor Antagonists Dextromethorphan and Dextrorphan with P-Glycoprotein
Volume: 9 Issue: 2
Author(s): Jules Desmeules, M. Kanaan, Y. Daali and P. Dayer
Affiliation:
Keywords: P-glycoprotein, Caco-2 cells, Transport, Dextromethorphan, Dextrorphan
Abstract: The anti-N-methyl-D-aspartate (NMDA) effect of dextromethorphan (DEM) seems to be mainly related to the unchanged drug rather than to its more potent metabolite dextrorphan (DOR). The aim of our study was to assess the involvement of P-glycoprotein (Pgp) and pH conditions in the transmembranal transport of these two NMDA antagonists, using a human in vitro Caco-2 cell monolayer model. Transmission electron microscopy, transepithelial electrical resistance, [3H]-mannitol permeability, Western blot analysis and the bidirectional transport of the positive controls, rhodamine and digoxine were used to confirm models integrity and validity. The bidirectional transport of DEM and DOR (1 to 100μM) across the monolayers was investigated in the presence and absence of the P-gp inhibitor cyclosporine A (10μM) at two pH conditions (pH 6.8/7.7-pH 7.4/7.4) and assessed with the specific and more potent P-gp inhibitor GF120918 (4μM). Analytical quantification was achieved using high performance liquid chromatography. At a pH gradient, DEM and DOR were subject to a significant active efflux transport (Papp(B-A) > 2-3x Papp(A-B); p < 0.01). However, neither the influx nor the efflux was affected by P-gp inhibitors. At physiological pH, we observed no more efflux of the drugs and no influence of the inhibitors. In conclusion, dextromethorphan and dextrorphan are not P-gp substrates. However, pH-mediated efflux mechanisms seem to be involved in limiting DEM gastrointestinal absorption. The preferential anti-NMDA central effect of DEM appears to be P-gp independent.
Export Options
About this article
Cite this article as:
Desmeules Jules, Kanaan M., Daali Y. and Dayer P., Lack of Interaction of the NMDA Receptor Antagonists Dextromethorphan and Dextrorphan with P-Glycoprotein, Current Drug Metabolism 2008; 9 (2) . https://dx.doi.org/10.2174/138920008783571765
DOI https://dx.doi.org/10.2174/138920008783571765 |
Print ISSN 1389-2002 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5453 |

- Author Guidelines
- Bentham Author Support Services (BASS)
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Suppression of TLR Signaling by Targeting TIR domain-Containing Proteins
Current Protein & Peptide Science New Approaches to the Modulation of the Cyclooxygenase-2 and 5-Lipoxygenase Pathways
Current Topics in Medicinal Chemistry Personalized Diabetes and Cancer Medicine: A Rationale for Anti-Diabetic Nutrition (Bitter Melon) in a Supportive Setting
Current Cancer Therapy Reviews Effect of an Obesogenic Diet During the Juvenile Period on Growth Pattern, Fatness and Metabolic, Cardiovascular and Reproductive Features of Swine with Obesity/Leptin Resistance
Endocrine, Metabolic & Immune Disorders - Drug Targets Melatonin in Bacterial and Viral Infections with Focus on Sepsis: A Review
Recent Patents on Endocrine, Metabolic & Immune Drug Discovery (Discontinued) Understanding Cancer Drug Resistance by Developing and Studying Resistant Cell Line Models
Current Cancer Drug Targets Development of Vascular Endothelial Growth Factor Receptor (VEGFR) Kinase Inhibitors as Anti-Angiogenic Agents in Cancer Therapy
Current Medicinal Chemistry Predictive Molecular Markers of Response to Epidermal Growth Factor Receptor(EGFR) Family-Targeted Therapies
Current Cancer Drug Targets Metabolite Quantification in Tumours by Magnetic Resonance Spectroscopy: Objectives, Results and Perspectives
Current Medical Imaging Inventions Designed to Enhance Drug Delivery Across Epithelial and Endothelial Cells Through the Paracellular Pathway
Recent Patents on Drug Delivery & Formulation Copper Chelation Chemistry and its Role in Copper Radiopharmaceuticals
Current Pharmaceutical Design Chronic Inflammation and Oxidative Stress as a Major Cause of Age- Related Diseases and Cancer
Recent Patents on Inflammation & Allergy Drug Discovery High Throughput Metabolomics in Clinical Studies: Review and New Applications to Remote Ischemic Preconditioning
Current Topics in Medicinal Chemistry Therapeutic Potential of Nucleic Acid-Based Drugs in Coronary Hyper- Proliferative Vascular Diseases
Current Medicinal Chemistry Prognostic and Predictive Molecular Markers in Cutaneous Malignant Melanoma: The First Step Toward Personalized Medicine
Current Pharmacogenomics and Personalized Medicine Non-squamous Tumors of the Oropharynx and Oral Cavity: CT and MR Imaging Findings with Clinical- Pathologic Correlation
Current Medical Imaging Dynamic Contrast-Enhanced Magnetic Resonance Imaging for Differentiating Between Primary Tumor, Metastatic Node and Normal Tissue in Head and Neck Cancer
Current Medical Imaging New Insights about the Potential Application of the Association of Vitamins C (Sodium Ascorbate) and K3 (Menadione) as Auxiliary Therapy in Cancer Treatment
Medicinal Chemistry Reviews - Online (Discontinued) Pathophysiology of IgG4-Related Disease
Current Immunology Reviews (Discontinued) Pharmacogenetics and Statin Treatment: Reality or Theory?
Current Vascular Pharmacology