Pharmacokinetics

• To produce its pharmacological effects, a drug must be present in appropriate concentrations at its sites of action
• The concentrations of active, free drug also depend on the extent and rate of absorption, distribution, metabolism (biotransformation), and elimination
• Pharmacokinetic Phase


  Drug membrane transportation
• Regardless of the route of administration a drug almost always must cross a biological membrane(s) to reach its site of action
• Absorption, distribution and elimination of a drug all require drug transport through membranes
• Modes of drug membrane transportation

  • Carrier-mediated transport
  • Passive diffusion
  • Active transport
• Passive diffusion


  • Most common and important mode of traversal of biological membranes
  • Molecules move down a concentration gradient
  • Does not expend energy
  • The rate of diffusion of uncharged drugs is determined primarily by lipid solubility
• Passive diffusion types


  1. Filtration

  2. Simple diffusion

  3. Facilitated diffusion
• Active transport


  • Transports molecules against a concentration gradient
  • Movement across the membrane is mediated by a carrier
  • A saturated process
  • Requires metabolic energy
• Carrier-mediated facilitated diffusion


  • A saturated process with a limited number of carriers
  • Specific for certain drugs
  • Requires no energy and cannot move against a concentration gradient
• Non-ionic drugs are more lipid soluble and can easily pass through cell membranes, while ionic drugs are restricted to one side of the membrane
• Ion trapping


  Principle that explains how non-ionic and ionic forms of a drug distribute across a membrane
• First-pass effect


  When an orally administered drug passes initially through the hepatic circulation and is metabolized before reaching the systemic circulation
• Bioavailability


  The fraction of unchanged drug reaching the systemic circulation following administration by any route
• For IV administration, bioavailability is 1.0
• Hepatoenteral circulation


  Drugs and metabolites are excreted to the intestine by bile and can be reabsorbed from the intestine
• Distribution


  Drug leaves the bloodstream and enters the interstitial and intracellular fluids
• Distribution is determined by many factors, one of which is plasma binding
• Blood-brain-barrier and placental barrier may affect the distribution of drugs
• Plasma protein binding


  • The binding of drugs to plasma proteins, which is usually reversible
  • The protein-bound fraction of a drug is inactive, while the "free" or unbound drug is active and exerts an effect
  • The extent of plasma protein binding is variable (0% to 99%)
  • Bound drugs cannot cross membranes and cannot be easily distributed
• Redistribution of drugs


  A drug can redistribute from the site of action to other organs where the drug has no pharmacological action, leading to storage and termination of the drug's effects
• Metabolism or biotransformation


  • The chemical structure of a drug is changed, usually to a more water-soluble form to enhance excretion
  • Most drug metabolism occurs in the liver
• Types of drug metabolism reactions

  • Microsomal oxidations
  • Non-microsomal oxidations (reductions, hydrolysis, conjugations)
• Microsomal enzymes, particularly the cytochrome P-450 enzyme system, play a predominant role in drug metabolism
• Enzyme inducers


  Drugs that increase the amount or activity of microsomal drug-metabolizing enzymes, accelerating the metabolism of the inducer and co-administered drugs
• Enzyme inhibitors


  Drugs that decrease the activity of microsomal drug-metabolizing enzymes, slowing the metabolism of the inhibitor and co-administered drugs
• Drug elimination


  The termination of a drug's effect, which is not the same as excretion
• Time-concentration curve and AUC

  The area under the curve (AUC) represents the total amount of drug that reaches the systemic circulation and is used to calculate bioavailability
• Absolute bioavailability


  The fraction of an administered dose of a drug that reaches the systemic circulation when given by a non-intravenous route, compared to intravenous administration
• Relative bioavailability


  The bioavailability of a test drug compared to a reference (standard) drug
• First-order kinetics


  A constant fraction of the drug is absorbed or eliminated per unit time
• Zero-order kinetics


  The same quantity of the drug is absorbed or eliminated per unit time
• Half-life (t1/2)


  The time taken for the concentration of a drug to fall to half of the initial value
• Apparent volume of distribution (Vd)

  A hypothetical volume that relates the amount of drug in the body to the concentration of the drug in the blood or plasma
• Steady-state concentration (Css)


  The concentration of a drug in the body that is maintained when the rate of administration equals the rate of elimination