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Pharmacokinetics and Biopharmaceutics > Distribution > Flashcards

Flashcards in Distribution Deck (11):
1

What is Volume of Distribution?

  • Volume of distribution simply relates the concentration of a drug in a fluid, typically plasma, to the amount in the body

2

What process is drug distribution?

  • Drug distribution is a passive process generally and so tissues and blood are in free equilibrium

3

What does Distribution out of the blood into tissues involve?

  • First involve the drug crossing the blood vessel wall typically via a combination of passive diffusion processes (easy for most drugs that are <5000 Da molecular weight, and is independent of change, molecular weight or ionisation)

    a. between junctions in the cells forming the wall (paracellular movement).

    b. across the cell membranes (transcellular movement).

  • Once this has occurred, then the drug is in the extracellular water (interstitial fluid ~ 12-15L).

4

After the drug has distributed out of the blood into the tissues what happens?

What would Vd equal if a drug is in free exchange across the cell membranes in the tissue?

What are tissue cell membranes compared to capillaries?

  • Drug might then cross tissue cell membranes (intracellular fluid)
  • If a drug is in free exchange across the cell membranes in the tissue, then the Vd would be = total body water (~42L = intra + extra- cellular fluid)
  • Tissue cell membranes are more restrictive than capillaries, and so lipophilicity/ionisation/molecular weight are more important here. Furthermore, different tissues have different cellular membrane characteristics.

5

What happens if a drug 'binds' to intracellular components (membranes, proteins, lipids etc: not necessarily 'target receptors/enzymes/etc')

  • It will accumulate inside tissue cells and as a result Vd will increase beyond total body water

6

What may the drug be bound to in the blood?

  • Drug may also be bound to plasma proteins in the blood (eg albumin)
    • any drug bound will not be able to diffuse out of the blood - this will act to reduce Vd

7

What may be affected by physicohemical properties of the drug and the physiology of the body?

  • A drug distributing into different tissues at different rates and to different extents

8

What changes in fraction unbound in the plasma (fu) and tissues (fut) do to Vd?

  • Increasing fu results in increasing Vd (drug is less restricted to the plasma/blood), while for fut this will decrease Vd (drug is less restricted to the tissues)
  • If Vd is >> than plasma volume, changes in fu and fut will result in almost proportionate changes in Vd. Typically we accept Vd to be >50L for this assumption

9

What is Vd determined by?

  • it's permeability across membranes and both tissue binding and plasma protein binding.  One must consider both aspects. For example:
    • a poorly lipophilic compound with a high fu might have a small Vd (eg lithium) because it cannot accumulate within tissue cells significantly.
    • a highly lipophilic compound with a low fu might have a large Vd (eg amiodarone). This is because the drug accumulates within tissues to a large extent, and it is also quite lipophillic.
    • a large molecule (eg a protein-based drug) might have a small Vd as it cannot diffuse out of the blood due to it's high molecular weight, irrespective of it's lipophilicity.

10

Distribution involves many Compartments

  • Blood (~5L/70kg; Plasma [~3L/70kg])
  • Many tissues each with
    • Extracellular fluid (~14/15L)
    • Intracellular fluid (~30L)
    • Total body water ~42L/70kg

11

All Vd's are determined by the interaction between:

  • Physiochemical properties of the drug
  • Physiological factors of the body

Elaborate .. 

  • Physiochemical properties of the drug
    • lipophilicity
    • ionisation
    • molecular size
  • Physiological factors of the body
    • rate of delivery (tissue blood flow)
    • binding to plasma/blood proteins (or cells)
    • binding to tissue 'structures' (membranes, intracellular components)
    • active transport (mainly efflux from the tissue)