Drug Absorption and Distribution

Fates of drug absorption in the body

  • Absorption: drug is absorbed from site of administration, entry into the plasma
  • Distribution: drug leaves bloodstream and is distributed into interstitial and intracellular fluids
  • Metabolism: drug transformation by metabolism - liver and other tissues
  • Excretion: drug and/drug metabolites excreted in urine, faeces or bile

Movement of drugs across cell barriers

Passive diffusion

  • Directly through lipid/aquaporins
  • Drugs with high lipid solubility - high concentration gradient

Facilitated diffusion

  • Via specialized carrier proteins
  • Does not require energy
  • Movement is down a concentration gradient
  • Water-soluble drugs - otherwise would not be able to cross membrane = carrier required
  • Can show saturation kinetics - limited amount of carriers

Active transport

  • Via specialized carrier proteins
  • Requires energy
  • Can move molecules against concentration gradient
  • Water-soluble drugs
  • Can show saturation kinetics

Endocytosis

  • Invagination of a part of the membrane
  • Drug is encased in a small vesicle, then ‘released’ inside the cell
  • Transport of large drugs across cell membrane

pH and ionisation

  • Only unionised forms readily diffuse across the lipid bilayer
  • Degree of ionisation depends on pKa of drug and the local pH
    • pKa: pH at which 50% of the drug is ionized and 50% is unionised
  • Henderson-Hasselbalch equation is used to determine proportions of ionized and unionised drugs in a given pH environment
    • pKa = pH + log(AH/A-)
    • Lower pKa (higher Ka) = strong acid
    • Allows you to determine how active a drug may be in the body

pH trapping

  • ‘Trap’ a particular drug based on its physiochemical property in compartments that have a particular pH
  • Weak bases accumulate in compartments with low pH (+ reverse)
  • Facilitates absorption at target

Volume of distribution

Apparent volume of distribution (Vd)

  • Vd: extent to which a drug partitions between the plasma and tissue compartments
    • Low Vd = drugs retained in vascular compartments
    • High Vd = drugs retained in non-vascular compartments – adipose, muscle etc.
  • Largely determined by physiochemical properties

Plasma protein binding

  • Albumin is the most abundant plasma protein
  • Affects Vd
    • Reduces the ability of the drug for diffusion to target organ
    • May also reduce transport of the drug to non-vascular components