IC9

• Pharmacokinetic processes


  1. Absorption

  2. Distribution

  3. Metabolism

  4. Excretion
• Absorption


  Occurs when the unchanged drug proceeds from site of administration to site of measurement within the body (usually plasma in arm vein)
• Absorption


  • This is for extravascular administration --> absorption is systemic
• Distribution


  Occurs after systemic absorption, drug gets distributed via systemic circulation to various tissues and organs in the body
• Distribution


  • Cell-to-cell distribution (through bile etc)
  • Rate and extent of distribution may differ for different sites considering biological, genetics, environmental differences
• Metabolism and excretion


  • Drug is eliminated, which is the irreversible loss of drug from the site of measurement
  • Liver: converting one chemical species to another [METABOLISM]
  • Kidney: irreversible loss of chemically unchanged drug [EXCRETION]
• Factors affecting drug movement across a membrane

  1. Passive transcellular

  2. Paracellular

  3. Facilitated transcellular
• Passive transcellular


  • Transport occurs down a concentration gradient
  • Occurring until unbound concentration equilibrium is reached
• Paracellular


  • Transport occurs between cells
• Facilitated transcellular


  • Active transport
  • ATP-dependent: transport against concentration gradient
  • Directional
  • Influx (uptake) or efflux transporters
• Drug must be in solution before it can cross the membrane
• Drug must be unbound to proteins or other solutes
• Factors affecting drug movement across a membrane

  • Physiochemical: Size of drug molecule
  • Lipophilicity
  • Charge
  • Solubility
• Oral bioavailability (F)


  Fraction of an orally administered drug that reaches systemic circulation
• FF


  Fraction that enters intestinal tissues (neither lost in the feces nor decomposed in the lumen)
• FG


  Fraction that reaches portal vein (escapes destruction within the walls of GIT, metabolized by drug metabolizing enzymes)
• FH


  Fraction that reaches liver but escapes extraction within the liver
• Factors that affect bioavailability

  • First-pass metabolism
  • Loss for drug via enzymatic or non-enzymatic within gut lumen or in the intestinal epithelium
• Apparent volume of distribution (V)


  • Fluid volume in which a drug seems to be distributed to account for its plasma concentration
  • Relates the amount of drug in the body to the concentration of drug C in blood or plasma
  • V = Amount of drug in body / C
• Apparent volume of distribution (V)

  • V may be defined wrt to blood, plasma or water
  • With reference to unbound drug
• Clinical applications of apparent volume of distribution

  • To know distribution characteristics of a drug
  • Protein drugs have V close to plasma volume due to their large molecular size --> unable to cross cell membrane to be distributed to tissues
  • Basic compounds tend to have large V than acids so they are more distributed within the fluid
• Unbound fractions


  • Blood/plasma
  • Tissues
• Equilibrium


  • Bound-unbound drug in plasma/blood
  • Bound-unbound drug in tissue
  • Equilibrium between blood and tissue compartments
• Bound-unbound drug in plasma/blood

  • Different drug binding plasma proteins or proteins have different abundance, drug selectivity, binding affinity
  • Albumin is most abundant
  • Acidic (anionic) drugs: tend to bind exclusively to albumin, tend to have smaller V
  • Basic (cationic) drugs: bind to albumin and lipoproteins, lipophilic amines have a selective affinity for lipophilic amines, glycoproteins, lipoproteins and albumin, larger V
• Clinical application of drug-protein binding


  • Only free drug can be distributed or eliminated
  • Changes in Fu may alter primary PK parameters (CL, V, F), ultimately affect the overall disposition of the drug in the body