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BIOAVAILABILITYTime course of drug in the body: route of drug administrationOral vs IV injectionReasons for differences: completeness and rate of absorption Definition: rate and extent to which a drug substance or its active moiety is delivered from the dosage form to the systemic circulation
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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
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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
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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
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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 ofLayer 1: perturbed water layerLayer 2: hydrophilic/hydrophobic layer including bound water, lipid polar head groups and parts of the upper acyl chainsLayer 3: conformationally ordered acyl chain segmentsLayer 4: conformationally disordered acyl chain segments
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Membrane asymmetryMovement 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
•
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The effect of sterols on membrane fluidity Membrane proteins• Integral membrane proteins• Peripheral membrane proteins• Lipid anchored membrane proteinsMembrane protein asymmetryLipid protein interactions: hydrophobic
matching, lipid sorting and lipid selectivity
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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
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Controlled by Fick’s Law of diffusion dQ = DAK (CGI-Cplasma)
dt hdQ/dt = rate of diffusionD = diffusion coefficientA = surface area available for diffusionK = lipid-water partition coefficienth = membrane thicknessC1 and C2 are the conc. at both sides of the membrane
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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
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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)
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II Carrier mediated transportSpecialized 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
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Facilitated diffusion, facilitated transport• Carrier mediated, transmembrane, • No energy, downhill• Minor role in drug absorption• Saturable
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Carrier mediated vs. Passive diffusion1. 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)
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• 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
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III Paracellular • Across tight junctions between the cells• Molecular size limitationVI 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: particlesPhagocytes, macrophages • Pinocytosis: nonselective uptake of droplets
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• Receptor mediated endocytosis: highly selective endocytosisTransferrin, vitamins, hormones, LDL, antibodies
BindingVesicle formation: clathrin coated vesicleUncoatingFusion with an early endosomeRecyclingDegradationTranscytosis
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• Potocytosis: caveolae
• VII P-glycoprotein (permeability glycoprotein)ATP dependent efflux pump
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