Download BIOAVAILABILITY Membranes

BIOAVAILABILITY
Time course of drug in the body: route of
drug administration
Oral vs IV injection
Reasons 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
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
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
Nature of cell membranes
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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
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
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
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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
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
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
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
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)
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
Facilitated diffusion, facilitated transport
• Carrier mediated, transmembrane,
• No energy, downhill
• Minor role in drug absorption
• Saturable
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)
• 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
III Paracellular
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Across tight junctions between the cells
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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
• 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
• Potocytosis: caveolae
• VII P-glycoprotein (permeability glycoprotein)
ATP dependent efflux pump