1. Absorption definition
    All processes from the site of administration to the site of measurement
  2. Intravascular definition
    Placement of drug molecule directly into the blood stream (i.v.)
  3. Extravascular definition
    Oral, sublingual, subcutaneous, rectal, intramuscular administration
  4. Bioavailability definition
    The fraction of an extravascularly administered drug which reaches the circulation intact. Represented by F

    (measure of the extent of absorption of unchanged drug)
  5. Absolute bioavailbility
    Assessed with reference to an i.v. dose
  6. Relative bioavailability definition
    Comparison of the bioavailability between formulations of a drug given either by the same or different routes of administration
  7. Bioequivalence definition
    Formulations containing the same dose of the same chemical entity, generally in the same dosage form, intending to be interchangeable

    Have to be within limits (usually +/- 20% around reference product - not necessarily exactly the same
  8. Rate limiting steps for oral absorption
    Disintegration time

    Dissolution rate

    Movement through membranes (perfusion or permeability limitations)

    Gastric emptying

    Intestinal transit

    First pass metabolism in gut/liver
  9. Movement through a cell


    Efflux transporters
  10. Transcellular
    Through the cell

    Passive diffusion, active transport or facilitated transport

    - dependent on conc gradient

    - transport continues until equilibrium is reached

    Dependent on;

    - Lipophilicity

    - Molecular size

    - Degree of ionisation

    - Molecular structure (H-donor/acceptor, functional groups)

    - Surface area available (varies along gut)
  11. Paracellular
    Between the cells

    Passive diffusion

    - Important for polar, hydrophilic molecules

    - Dependent on molecular size, size and density of junctions, surface area
  12. Efflux transporters
    e.g. P-glycoprotein

    Can reduce oral absorption as a result of efflux in the intestinal lumen
  13. Perfusion rate limitation
    Membrane offers no effective barrier to drug

    Molecule readily passes across membrane

    - small, lipophilic molecules

    - very small hydrophilic molecules

    Absorption rate varies with blood flow
  14. Membrane permeability rate limited absorption
    Molecule has difficulty passing through membrane

    Absorption insensitive to changes in blood flow

    Large, polar hydrophilic molecules

    e.g. gentamycin, streptomycin, vancomycin, cefotaxamine, pyridostigmine
  15. Intramuscular/subcutaneous absorption
    Barrier different to gut wall

    Major difference in paracellular route - pores larger - more readily absorbed compared to oral

    Generally perfusion rate limited irrespective of polarity and pka of compound
  16. Drug release from formulation
    2 options

    Release/dissolution rate limited (more common)

    Permeability rate limited absorption
  17. Rate limitations along the gut
    Permeability changes along GIT affect changes in rate limitation

    Important for sustained release formulations

    Poorly permeable drugs not good candidates for extended release formulations
  18. Intestinal absorption - factors affecting
    Surface area

    Blood flow


    All greater for small intestine compared to the stomach

    All drugs in solution are absorbed faster in small intestine, even acids
  19. Effects of drugs on the rate of gastric emptying
    Metoclopramide - increases gastric emptying

    Anticholinergic - reduces gastric emptying

    Only rate is affected, not extent
  20. Effect of food on gastric emptying
    Fasted - fast delivery to upper small intestine, no major difference between particle sizes

    Fed - delayed gastric emptying, affects rate of absorption, difference between particle sizes

    Small intestine - food has no effect on transit time in the small intestine, no difference between different particle sizes
  21. Causes of incomplete absorption
    Lack of time (esp oral route) - due to;

    - low intestinal permeability with large polar molecule (e.g. neomycin)

    - poor dissolution (solubility)

    Competing reaction

    - enzymatic (intestinal P450, interplay with efflux transporters)

    - non-enzymatic (complexation)

    Intestinal and hepatic extraction

    - for orally administered drugs
  22. Drugs with low bioavailability due to high first pass effect










  23. What does the rate of distribution depend on?
    Delivery of drug to tissue by perfusion

    Tissue membrane permeability

    Binding of drug to plasma and tissue components and partitioning into fat
  24. Which parts of the body and well perfused?
  25. Which parts of the body are poorly perfused?
  26. Rate of distribution: Perfusion rate limitation
    Occurs when the membrane separating the blood from the tissues is not a barrier to drug distribution

    Likely to occur with small and lipophilic molecules distributing across thin membranes
  27. Rate of distribution: permeability rate limitation
    Likely to occur with polar molecules and relatively impermeable membranes
  28. Rate of distribution: location of uptake barrier
    Muscle, kidney - capillary porous, barrier at cellular level

    CNS - barrier at capillary level
  29. Apparent volume of distribution
    Apparent volume that a drug occupies at a concentration equal to that in the plasma

    Hypothetical - rarely a physiological space (e.g. total body water)

    Can vary from 7-50000L+/70kg

    Relates measured plasma drug conc (C) to the amount of drug in the body (A)

    V= A/C
  30. What does apparent volume of distribution depend on?
    Reference fluid measured (plasma, blood, unbound drug)
  31. Pharmacokinetics: definition
    How the body handles the drug
  32. Pharmacodynamics: definition
    What the drug does to the body
  33. Distribution: definition
    Reversible transfer of substance between site of measurement and other sites within the body
  34. Metabolism: definition
    Irreversible loss of unchanged substance by chemical conversion
  35. Excretion: definition
    Irreversible loss of unchanged substance
  36. Elimination: definition
    Irreversible loss of unchanged substance from site of measurement
  37. Disposition: definition
    Elimination and distribution
  38. First pass effect: definition
    Low oral bioavailability caused by loss of drug as it passes through eliminating organs/tissues (intestinal wall/liver) for the first time before entering the systemic circulation
  39. What are the applications of pharmacokinetics?
    Relates patterns of response (efficacy, toxicity) to drug administration following acute and chronic dosing

    Helps provide a rational basis for drug design, selection and dose regimen design

    Helps quantitatively evaluate drug product performance in vivo and establish appropriate in vitro dissolution specifications

    Provides a means for comparing data from different animal species
  40. Distribution phase: definition
    The time period which the drug in all the tissues comes into distribution equilibrium with the drug in the plasma

    This occurs sooner with highly perfused tissues

    Usually completes within 30 min to 5 hours - elimination during this phase is usually small
  41. Elimination phase: definition
    The time period when decline in concentration (C) reflects proportional loss from the body

    It is characterised by t1/2 and V (vol of dist)
  42. Volume of distribution: definition
    The apparent dilution space into which the drug distributes
  43. Elimination t1/2: definition
    The time taken for the plasma concentration (as well as amount in the body) to fall by one half, once distribution elimination has been achieved
Card Set
Pharmacokinetics 4th year