1. 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

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

4. 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

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

6. 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

7. 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

8. 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

9. 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

10. 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

11. 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

12. 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)

13. 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

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

16. 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 Km
(1st order kinetics)

17. 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

19. 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

20. Vesicle formation: clathrin coated vesicle Uncoating
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

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