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Estimating bioavailability

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Estimating bioavailability

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  1. BIOAVAILABILITYTime course of drug in the body: route of drug administrationOral vs IV injectionReasons for differences: completeness and rate of absorptionDefinition: rate and extent to which a drug substance or its active moiety is delivered from the dosage form to the systemic circulation

  2. Estimating bioavailability • Absolute bioavailability, AUC estimates from extravascular and IV administration • Relative bioavailability Characteristics to be investigated: • Shape and area of the plasma concentration vs time curve • AUCt, AUCinfinity, Cmax, Tmax Estimating the rate of absorption • Important for drugs that need prompt therapeutic effect • Cmax and Tmax

  3. Physiologic Factors Related to Drug Absorption The systemic absorption of drugs is dependent on • Physicochemical properties of the drug • Nature of drug product • Anatomy and physiology of the absorption site

  4. Nature of cell membranes • Important barrier to drug delivery • Major structure of cells • Enclose cellular content and organelles • Semipermeable partitions, selective barriers • Thin, 70-100 A • Composed primarily of phospholipids, carbohydrates and proteins

  5. Theories of cell membrane structure • The Lipid Bilayer or Unit Membrane Theory (1952): considers the membrane as lipid bilayer with proteins on the surface !! explains transport of lipophilic substances, but not hydrophilic ones • Fluid Mosaic Theory (1972) • Lipid membrane structure in relation to drug research Stratified layer composed of Layer 1: perturbed water layer Layer 2: hydrophilic/hydrophobic layer including bound water, lipid polar head groups and parts of the upper acyl chains Layer 3: conformationally ordered acyl chain segments Layer 4: conformationally disordered acyl chain segments

  6. Membrane asymmetry Movement of lipids in the bilayer is either • Flip flop or transverse diffusion and this is not common • Rotation of the phospholipids about their long axis: very common • Lateral diffusion in the plane of the membrane

  7. The effect of sterols on membrane fluidity Membrane proteins • Integral membrane proteins • Peripheral membrane proteins • Lipid anchored membrane proteins Membrane protein asymmetry Lipid protein interactions: hydrophobic matching, lipid sorting and lipid selectivity

  8. Transport of drugs across cell membranes I Simple or passive diffusion • Spont. high conc. to low conc. • Passive: no energy consumption • Basis: lipid solubility, conc. gradient • Rate of transport = flux, vector • Major absorption process for drugs

  9. Controlled by Fick’s Law of diffusion dQ = DAK (CGI-Cplasma) dt h dQ/dt = rate of diffusion D = diffusion coefficient A = surface area available for diffusion K = lipid-water partition coefficient h = membrane thickness C1 and C2 are the conc. at both sides of the membrane

  10. Factors influencing passive diffusion • D: constant for each drug molecule (cm2/sec) • h: constant for a particular absorption site • K: hydrophobic vs. hydrophilic • A: surface area available for transport

  11. Assuming that: 1. D, A, K, and h are constants for a specific membrane, specific drug, the Permeability coefficient (P) could be defined P = DAK h  2. C1>>>>>>>C2  dQ/dt = P (C1) (1st order kinetics)

  12. II Carrier mediated transport Specialized carrier mediated transport systems Active transport • Carrier mediated, transmembrane, energy requiring • Against conc. gradient • GI absorption, renal and biliary secretion • 5 fluorouracil • High selectivity • Saturable

  13. Facilitated diffusion, facilitated transport • Carrier mediated, transmembrane, • No energy, downhill • Minor role in drug absorption • Saturable

  14. Carrier mediated vs. Passive diffusion 1. No. of carriers • Rate of transport (Michaelis-Menten) • Rate of absorption = Vmax C Km + C • C= solute conc. at the absorption site • Vmax and Km = constants • at low conc. Km>>>>>>>>>>C • Rate of absorption = Vmax C Km (1st order kinetics)

  15. at higher conc. C>>>>>>>>>>>Km • Rate of absorption = Vmax • Difference in the plots rate of transport vs. drug concentration at absorption site • Selectivity and specificity • Competition • Inhibition: cellular metabolism

  16. III Paracellular • Across tight junctions between the cells • Molecular size limitation VI Vesicular transport • A vesicle: small spherical membranous sac formed by budding off from an existing membrane • Endocytosis and Exocytosis • Endocytosis • Material is brought into the cell • Phagocytosis: particles Phagocytes, macrophages  • Pinocytosis: nonselective uptake of droplets

  17. Receptor mediated endocytosis: highly selective endocytosis Transferrin, vitamins, hormones, LDL, antibodies  Binding Vesicle formation: clathrin coated vesicle Uncoating Fusion with an early endosome Recycling Degradation Transcytosis

  18. Potocytosis: caveolae • VII P-glycoprotein (permeability glycoprotein) ATP dependent efflux pump

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