Mechansim Of Drug Transport

Translocation of Drug Molecules

• By bulk flow transfer (convective transport):
  • Occurs in the bloodstream.
  • Provides a very fast, long-distance distribution system for all solutes, irrespective of their chemical nature.
• By diffusional transfer:
  • Involves molecule-by-molecule transfer (short-distance).

• The transfer of drug molecules occurs across cell membrane barriers that separate the various aqueous compartments of the body.
  • Drugs exist in these compartments in both bound and free forms, except in fats (where they are in free form).
  • The free form of the drug can move between compartments.
  • The movement and availability of drugs at the site of action depend upon:
    • Molecular size and shape.
    • Degree of ionization.
    • Relative lipid solubility of ionized and non-ionized forms.
    • Binding to serum/tissue proteins.

Structure of Cell Membrane

• Bilayer of amphipathic lipids (both hydrophilic and hydrophobic portions).
  • Hydrophilic heads face outwards.
  • Hydrophobic hydrocarbon chains face inwards, forming a continuous hydrophobic phase.
• Dynamic Nature:
  • Lipid molecules move laterally.
  • Cholesterol molecules integrate to provide:
    • Fluidity.
    • Flexibility.
    • Organization.
    • High electrical resistance.
    • Relative impermeability to highly polar molecules.
• Membrane Proteins:
  • Embedded within the lipid bilayer.
  • Act as receptors, ion channels, or transporters.
  • Involved in electrical or chemical signaling pathways.
  • Provide selective targets for drug action.

Mechanisms of Drug Transport

1. Simple Transfer
   • Movement of drugs from higher to lower concentration.
   • Two types:
     a) Passive membrane transport (simple diffusion).
     b) Filtration.
2. Facilitated Transport
   • Involves energy expenditure or carrier molecules (or both).
   • Three types:
     a) Active transport.
     b) Facilitated diffusion.
     c) Pinocytosis.

Passive Diffusion

• Drug diffuses across the membrane along its concentration gradient.
• Membrane plays no active role.
• It is the most important mechanism for the majority of drugs.
• Lipid-soluble drugs:
  • Dissolve in the lipoidal matrix of the membrane.
  • Rate of transport is proportional to the lipid:water partition coefficient.
  • More lipid-soluble drugs achieve higher concentration in the membrane and diffuse quickly.
• The greater the concentration gradient, the faster the diffusion.

Filtration (Diffusion through Aqueous Channels)

• Passage of drugs through aqueous pores/channels.
• Most cells have small pores (about 4 Å).
• Very small particles (molecular size < 100) or polar/non-polar substances can be filtered with the bulk flow of water driven by hydrostatic pressure or osmotic differences.
• Capillary endothelial cells (except in the brain):
  • Separated by slits (~40 Å) that allow filtration of many large molecules.

Active Transport

• Energy-dependent and carrier-mediated process.
• Transport occurs against the concentration or electrochemical gradient (from lower to higher concentration).
• Structure-specific: carriers transport drugs with specific chemical structures.
• Drugs with similar structures compete for the same carrier.
• Types of Active Transport:
  a) Primary active transport: One substance is carried against its gradient.
  b) Secondary active transport: Two substrates are involved:
  • Driving solute (e.g., Na⁺, K⁺, Ca²⁺) moves along its gradient.
  • Actual substrate moves against its gradient.
  • Cotransport (symport): Both substrates move in the same direction (e.g., Na⁺-glucose cotransport in the GIT).
  • Counter transport (antiport): Substrates move in opposite directions (e.g., Na⁺-H⁺ exchange).

Facilitated Diffusion

• Carrier-mediated passive transport along the concentration gradient (downhill movement).
• No energy requirement (driven by the gradient).
• Faster than simple diffusion and can transport non-diffusible substances.
• Structure-specific and saturable.
• Subject to competition by structurally similar agents.
• Not a major mode of drug transport (e.g., glucose transport in RBCs, intestinal absorption of vitamin B1).

Pinocytosis

• Involves engulfing extracellular materials by the cell membrane to form vesicles.
• Vesicles are pinched off and release engulfed particles intracellularly.
• Energy-dependent like active transport.
• Low-order structure selectivity.
• Competitive and saturable process.
• Important for uptake of macromolecular nutrients (e.g., fats, starch, proteins, fat-soluble vitamins like A, D, E, K) and certain drugs (e.g., insulin, poliovaccine).