Pharmacodynamics & Pharmacokinetics Principles

• Lecture 11 discusses the principles of pharmacodynamics and pharmacokinetics
• The objectives are to identify components of cell membranes and transport mechanisms across biological barriers, discuss the influence of ionization on passive diffusion of drugs, and discuss carrier-mediated transport and transport types

Transport Across Biological Barriers

• Cell membranes are composed of phospholipids arranged in a bilayer
• Phospholipids have a hydrophilic (polar) head and hydrophobic (nonpolar) fatty acid tails
• The fluid mosaic model describes the cell membrane as a fluid structure with various proteins embedded within it

Cellular Proteins in the Lipid Layer

• Soluble proteins include plasma proteins and enzymes
• Membrane proteins can be integral or transmembrane
• Transmembrane proteins include marker proteins, receptor proteins, and transport proteins
• Marker proteins identify cells to each other
• Receptor proteins transmit signals from the exterior to the interior of the cell
• Transport proteins include channel proteins, which create a channel or pore, and carrier proteins, which bind and transport substrate

Mechanisms of Transport

• The three primary mechanisms of transport across a semipermeable cell membrane are passive diffusion, carrier-mediated transport, and endocytosis and exocytosis
• Passive diffusion involves small molecule solutes and is the main mechanism for drugs
• Carrier-mediated transport involves both small and large molecules of appropriate properties
• Endocytosis and exocytosis involves macromolecules such as proteins and particles like viruses and bacteria

Passive Diffusion

• Passive diffusion is the movement of solute from higher to lower concentration until equilibrium is reached
• Passive diffusion does not require energy
• Water soluble molecules
• Solute may cross by diffusion through the lipid layer or through hydrophilic pores created by transmembrane channel proteins
• It is the major mechanism of transport for drugs

Rate of Passive Diffusion

• Fick's Law describes the rate of passive diffusion
• dC/dt = (P * A * D (C1-C2))/h
• P is the partition coefficient
• A is the surface area
• D is the diffusion coefficient
• h is the thickness
• C1 is the extracellular concentration of unionized solute
• C2 is the intracellular concentration of unionized solute
• The negative sign denotes a decrease in donor side concentration with time

Passive Diffusion of Weak Acids and Weak Bases

• The concentration gradient of the unionized form is the driving force
• When pH on donor and receiver side is the same as the pKa of the drug, weak acid and weak base molecules will diffuse until equilibrium is reached
• The Henderson-Hasselbalch equation calculate the ratio between the ionized and unionized forms of a drug if the pKa of the drug and pH of the solution are known

Ion Trapping

• Ion trapping occurs when the pH on the donor and receiver side is different
• Solute is trapped on the side of greater ionization at equilibrium
• Weakly basic drugs such as chloroquine can get concentrated by 100X in acidic vacuoles

Carrier-Mediated Transport

• Transporters are integral membrane proteins with one or more active sites for polar substrate
• Transporters do not require the substrate to be lipophilic
• Two major types of carrier-mediated transport are facilitated diffusion and active transport

Facilitated Diffusion

• Facilitated diffusion is a carrier-mediated process that occurs only when there is a concentration gradient between the donor and receiver
• It does not require energy
• An example is GLUT1 for glucose (polar compound)

Active Transport

• Active transport is similar to facilitated diffusion but can occur against a concentration gradient
• It requires an active energy source
• Uniporter transports only one type of molecule
• Antiporter transports two or more different molecules in opposite directions
• Symporter transports two or more molecules in the same direction

Drug Efflux & MDR Transporters

• Efflux pumps or transporters remove toxic solutes out of the cell
• They require ATP and provide a barrier to the uptake of xenobiotics
• A single type of transporter, Multidrug Resistance Transporter (MDR) can recognize and pump out many different types of drugs, limiting their effectiveness
• MDR transporters include P-glycoprotein and the Multidrug Resistance Protein (MRP)

Endocytosis & Exocytosis

• Endocytosis and exocytosis are vesicular transport processes
• They can occur against a concentration gradient
• They require cellular energy
• Endocytosis includes phagocytosis, pinocytosis, and receptor-mediated endocytosis

Transport Across Tissues

• Transcellular transport occurs when drug or other molecules pass through the cell layer
• Paracellular transport occurs when drug or other molecules pass through the aqueous space between the cells

Drug Transport Across Endothelium

• Endothelium is a specialized epithelium forming walls of blood vessels etc.
• They are more loosely packed than epithelial cells
• Gaps between cells contain a loose network of proteins that act as filters
• Paracellular pathway is more important for transport of drugs across the endothelium
• Capillary endothelial junctions are ~ 5 – 30 nm
• Molecules up to Mol. Wt. ~ 30K can diffuse
• Examples include blood-brain barrier (BBB)

Review Points

• Discussed was the composition, organization, and function of the lipid bilayer
• Discussed was the membrane transport, mechanisms, and proteins involved
• Discussed was passive diffusion and factors affecting the process
• Discussed was carrier-mediated transport, transport across tissue barriers, and the blood-brain barrier