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Membranes and TRANSPORT Processes

This lecture covers membrane transport mechanisms, including passive diffusion, facilitated diffusion, active transport, and transcytosis, and explores factors influencing permeability and transporters. It discusses protein-mediated vs. passive transport, important transporters in pharmacokinetics, and drug delivery methods like transcytosis and directed-drug delivery. The session also delves into biologics, drug development techniques, and adverse drug reactions.

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Membranes and TRANSPORT Processes

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  1. Lecture #6 Membranes and TRANSPORT Processes

  2. permeability Membrane

  3. Transport Types Protein-Mediated Transcytosis (Macromolecules) drug-bound protein caveolae

  4. Transport Types • Paracellular • Transcellular • Diffusion (Small Molecules) • Protein-Mediated (Small Molecules) • Transcytosis (Macromolecules)

  5. Diffusion Transcellular: Passive Diffusion

  6. Factors that Influence Passive Diffusion Permeability Hydrophobicity

  7. Factors that Influence Passive Diffusion: pH partition hypothesis

  8. Permeability Properties * Except testes, placenta and CNS.

  9. Permeability Hydrophobicity

  10. Passive Transport Active Transport Membrane Membrane Equilibrative Concentrative

  11. Protein-Mediated Transcellular Active Transport (Energy-Dependent) Facilitated Diffusion (Energy-Independent) Equilibrative Transporters Concentrating Transporters

  12. Regulation of Facilitated Diffusion • Voltage-gated • Ligand-gated • Mechanically-gated • Light-gated • Ligand-gated Transporter • GABAA receptor Pore Closed Pore Open

  13. Active Transport • Primary • ATP • Secondary • Electrochemical Gradient (ion-coupled) Peptide Transporter (Secondary) Multidrug Resistance Protein (Primary)

  14. Classes of Protein Transporters • Carriers • active (energy-dependent) or passive (energy-independent) • bind solute on one site and release it on the other • Channels • passive (energy-independent) • solutes diffuse through the protein Channel Carrier

  15. Differences Between Passive and Protein-Mediated Transport Not Saturable Channels and Passive Diffusion Transport Rate Saturable Carriers [Drug], mg/L

  16. Modes of Transport Coupled Transport cotransporter (symporter) exchanger (antiporter) uniporter A B C

  17. Most Important Transporters in PK BCRP = Breast Cancer Resistance Protein LAT = Large Neutral Amino Acids Transporter OAT = Organic Anionic Transporter OATP = Organic Anionic Transporting Polypeptide OCT = Organic Cationic Transporter MDR = Multidrug Resistance Protein MRP = Multidrug Resistance Protein SVCT = Sodium-Dependent Vitamin C Transporter

  18. Transporters ASBT = Ileal Apical Sodium/Bile Acid Co-Transporter BCRP = Breast Cancer Resistance Protein OAT = Organic Anionic Transporter OATP = Organic Anionic Transporting Polypeptide OCT = Organic Cationic Transporter MATE = Multidrug and Toxin Extrusion Protein MCT = Monocarboxylic Acid Transporter MDR (P-gp) = Multidrug Resistance Protein MRP = Multidrug Resistance Protein PEPT = Peptide Transporter URAT = Urate Transporter http://www.ncbi.nlm.nih.gov/pubmed/20190787

  19. [Drug] varies with Tissue Volume Distribution (V) = 122 L Blood Plasma HIV Protease Inhibitor [Drug], nM [Drug], nM Blood Plasma Brain Brain

  20. Distribution Rate varies with Tissues Drug Amount, ug

  21. Drugs: Biologics • Not typically produced by chemical synthesis and macromolecules originating from a biological organism • Extracted from living systems • Antibodies • Pig insulin • Heparin (Sugar) • Protein from Recombinant DNA (modified/unmodified) • Erythropoietin • Human growth hormone • Blood clotting factors • Engineered Viruses • Gene Therapy • Oncolytic Virus • DNA/RNA • Vaccines • Control Gene Expression Are engineered viruses drugs?

  22. Transcytosis Transcytosis of IgA, an immunoglobin

  23. Transcytosis Mechanisms Caveolae-Mediated (Receptor Independent) Clathrin-mediated (Receptor-Dependent) Other Proteins Involved AP2=Adaptor Protein 2 Receptor-mediated Transcytosis Absorptive Transcytosis

  24. Methods: Drug Delivery and Transcytosis Targeting Vector Biotin Drug • Chemical Linkage to Targeting Vector • Non-covalent streptavidin/biotin linkage • Biotin  streptavidin (1-10 fM) • Biotinylated drug  Streptavidin-Targeting Vector • Liposome with Targeting Vector • Drug inside liposome • Nanoparticles (polymers) • Coated for drug delivery Streptavidin

  25. Targets: Drug Delivery and Transcytosis • Transferrin Receptor • Transferrin-Drug • Insulin Receptor and Insulin-like Growth Factor Receptor • Insulin-Drug • Low Density Lipoprotein Receptor Related Proteins 1 and 2 • LDL (Drug Inside) • Diphtheria toxin receptor/Heparin binding epidermal growth factor • Non-toxic diphtheria toxin mutant-Drug • Heparin-Drug

  26. Examples: Directed-Drug Delivery and Transcytosis • Melanotransferrin(Protein) (p97) • Covalently linked with anti-cancer drugs • GPI-anchor • Transferrin Receptor • Angiopeps (Peptide) • small/large molecule delivery • alpha-2-macroglobulin receptor • Leptin (Peptide) • Leptin receptor Glycosylphosphatidylinositol (GPI anchor)

  27. Distribution is Reversible artery Anti-arthritis Prodrug Activated Charcoal Known since early 1800s Adverse Drug Reaction (ADR): Severe Skin Reaction t1/2 = 2 weeks vein

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