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

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 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

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

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 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

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 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

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

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)

• 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 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

• Receptor mediated endocytosis: highly selective endocytosisTransferrin, vitamins, hormones, LDL, antibodies

BindingVesicle formation: clathrin coated vesicleUncoatingFusion with an early endosomeRecyclingDegradationTranscytosis

• Potocytosis: caveolae

• VII P-glycoprotein (permeability glycoprotein)ATP dependent efflux pump