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 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  

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 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 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

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

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